NCI - National Cancer Institute Grants

NCI - National Cancer Institute

PROJECT SUMMARY There is significant evidence of cancer-type specific patterns of sex hormone receptor expression and signaling in many central nervous system (CNS) tumors, often correlating with their high sex-specificity. This supports the hypothesis that sex hormone receptors play tumorigenic and pathologic roles across many CNS cancers. However, their mechanistic functions in CNS tumors remain largely unknown. This proposal seeks to address these knowledge gaps in 2 of these cancers: meningioma and glioblastoma (GBM). In Aim 1, I explore the mechanism underlying progesterone receptor (PR) expression and signaling in meningiomas, the most common primary intracranial tumors. Meningiomas are 2.7 times more common in females than in males, can arise in the setting of exogenous female hormone therapy, and 70% express high levels PR, suggesting female sex hormones may drive meningioma tumorigenesis. Using human meningioma xenografts in mice treated with clinically relevant doses of synthetic progestins, I developed a model of female sex hormone-driven meningioma. The data presented in this application suggest progestins induce PR expression, increase tumor growth, and reduce survival through a positive feedback mechanism that requires progesterone membrane component 1 (PGRMC1), a non-classical hormone receptor with pathologic roles in breast and endometrial cancers. The central hypothesis of my doctoral dissertation project is that progestin ligand activates PGRMC1 to drive expression of PR in meningioma through regulation of NFB transcriptional activity, and that PR drives meningioma growth through cytoplasmic activation of MAPK signaling and transcriptional activation of TNFSF11, TGFA, and IRS2. Through the remainder of my graduate work I will (i) validate the pathway through which PGRMC1 drives PR expression through ChIP-QPCR, luciferase reporter, and loss-of-function validation models, (ii) identify hormonal cofactors involved in PGRMC1 signaling, (iii) validate the roles of PR downstream targets in driving growth and proliferation in meningioma through gain- and loss-of-function models, and (iv) incorporate human proteomic data to define expression levels of proteins implicated in PR and PGRMC1 signaling pathways in human patients. In Aim 2, I outline the proposed direction of my postdoctoral studies, the characterization of sex hormone signaling pathways in GBM. The most malignant primary brain tumors in adults, GBM are often marked by high expression of androgen and estrogen receptors, yet limited and often contradictory functional data for these receptors in GBM has impeded the development of sex hormone-targeted therapeutics. For this project, I plan to (i) perform integrated proteomic and phospho-proteomic characterization of hormone signaling networks in GBM, (ii) characterize and mechanistically validate the pathways through which sex hormone signaling influences GBM pathology, and (iii) develop combination therapies targeting these signaling axes. Taken together, these projects will integrate genetics, biochemistry, and proteomics to characterize therapeutically vulnerable signaling pathways in meningioma and GBM.

NCI - National Cancer Institute

Abstract The ANCHOR Biorepository at the University of Arizona and now formally integrated into the AIDS and Cancer Specimen Resource (ACSR), is a critical infrastructure supporting translational research on HPV- associated anal neoplasia. Originating from the NIH-funded Anal Cancer/HSIL Outcomes Research (ANCHOR) study (NCT02135419), the biorepository contains over 675,673 biospecimens collected longitudinally from 10,537 participants, including serum, plasma, whole blood, anal swabs, and formalin- fixed paraffin-embedded (FFPE) tissue blocks. Its unique strength lies in the systematic, longitudinal collection of biospecimens from screened and randomized participants—including those in the observational arm—prior to treatment, thus preserving the natural history of HSIL progression to cancer or regression, respectively. The ANCHOR study successfully demonstrated that treatment of HSIL prevents progression to cancer resulting in the release of new guidelines for anal cancer screening. However, the lack of physicians skilled in anal high resolution anoscopy (HRA), a technique to diagnose and treat HSIL, requires further optimization of current screening, diagnostic and treatment guidelines. The ANCHOR Biorepository is an integral resource of the ANCHOR Correlative Science Studies addressing critical gaps in our understanding of the pathobiology of anal cancer, particularly among persons living with HIV (PLWH), as well as HIV-negative individuals disproportionately affected by anal cancer, especially women. In the context of public health, all people regardless of HIV status will benefit from optimized strategies for anal cancer screening and prevention, especially people with oropharyngeal cancer and women with cervical cancer. For the grant year 2025-2026, over 50,000 specimens have already been approved for use, with at least 20,000 more in planning. Operationally, the biorepository is maintained under strict GLP and CAP-accredited protocols. Stewardship activities include temperature- and humidity-controlled cold storage (47 active and backup units), rigorous QA/QC procedures, and comprehensive informatics through Freezerworks. Sample distribution is governed by project specific SOPs, LOI approvals by several committee including NIH-CTEP, and Material Transfer Agreements (MTAs). An integral initiative of the biorepository is the development of a digital pathology library, which will be offspring of over 4,000 FFPE tissue blocks to create a slide repository for remote pathology review, AI-driven diagnostics, and deep annotation of histopathologic features. By providing high-quality, deeply annotated biospecimens, the ANCHOR Biorepository advances research on anal HSIL and anal cancer across populations. It represents a gold-standard model for biobanking in HPVrelated malignancy research and will continue to be a cornerstone for future discovery in screening, prevention, and therapeutic strategies.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT - MECHANOSURVEILLANCE IN BREAST CANCER METASTASIS Metastatic breast cancer is a devastating disease that impacts the lives of tens of thousands of women each year. Unfortunately, the majority of treatment options for patients diagnosed with metastatic breast cancer are palliative. Current treatment strategies often target cancer cells’ genetic and biochemical abnormalities, but cancer cells also undergo profound changes in their biophysical properties such as cellular stiffness. Targeting biophysical properties offers exciting new therapeutic avenues, but the basic knowledge on the relationship between cancer cell stiffness and regulation of metastasis is incomplete. Emerging evidence suggests that cancer cell stiffness acts as a mechanical input for activation of cytotoxic lymphocytes that destroy cancer cells. Thereby, stiffness becomes an immune vulnerability of cancer cells during the metastatic cascade. This process, where mechanical inputs activate the immune surveillance, is termed mechanosurveillance and it is strongly regulated by the expression of Myocardin related transcription factors A and B (MRTFA/B) in cancer cells. Based on the published and the preliminary data, the overarching hypothesis of this project is that MRTFA driven calcium influx increases cancer cell stiffness and thereby activates mechanosurveillance during breast cancer metastasis. The long-term goal of this project is to determine the molecular mediators of MRTFA associated mechanosurveillance and thereby inform pharmacological methods to exploit this cancer cell vulnerability for better treatment of patients with metastatic breast cancer. The research design includes a set of interdisciplinary approaches, such as transcriptomic and genomic analyses of patient samples and cancer models, atomic force microscopy on patient derived xenograft organoids (PDXos) and on immunocompetent models of metastatic colonization, and histological analyses of human breast cancer metastases. The specific aims of this project are: 1) to determine the contribution of MRTFA driven calcium influx on cancer cell stiffness in PDXos, in vitro, and in situ mouse models by using atomic force microscopy and confocal microscopy. 2) to determine the degree of cytotoxic lymphocyte activation by MRTFA and the associated stiffness in vivo by using multiplexed imaging and machine learning on metastatic tissue samples from patients and by using flow cytometry in metastases in syngeneic mouse models. 3) to determine how to exploit MRTFA associated mechanosurveillance to target metastases by testing the impact of clinically relevant immune checkpoint blockade treatments on metastasis bearing mice. This work will uncover mediators of mechanosurveillance and demonstrate its prevalence in human cancer. Thus, results of this work will impact the immediate use of immune checkpoint blockade and the future strategies to enhance mechanosurveillance in patients with metastatic breast cancer.

NCI - National Cancer Institute

THE PURPOSE OF THIS REQUIREMENT IS TO PROVIDE REGULATORY SERVICES AND TECHNICAL SUPPORT TO THE DIVISION OF CANCER PREVENTION (DCP) AT THE NATIONAL CANCER INSTITUTE (NCI).

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. The development of targeted molecular therapies that inhibit mutant oncogenic proteins and immunotherapies that inhibit the PD- 1/PD-L1 pathway have improved outcomes for subsets of patients with NSCLC. However, targeted therapies are only effective against NSCLCs that harbor actionable genetic alterations. In addition, anti-PD-1/PD-L1 immune checkpoint inhibitors are most effective against NSCLCs that express high levels of PD-L1 or have a high tumor mutation burden. Thus, patients with NSCLCs that lack these features do not benefit from targeted therapies and are less likely to benefit from immunotherapies, emphasizing the need to identify novel therapeutic targets in this disease. This project seeks to characterize the XRN1 exoribonuclease, which functions in cellular RNA degradation, as a target that may have broad therapeutic potential in NSCLC. My preliminary data show that XRN1 inactivation induces cell lethality in a subset of human NSCLC cell lines. In an implantable mouse tumor model, XRN1 deletion can synergize with anti-PD-1 immunotherapy to enhance tumor eradication. Aim 1 will define the molecular signaling pathways that mediate cell lethality after XRN1 deletion in a subset of human NSCLC cell lines. Aim 2 will assess the impact of XRN1 deletion in mouse NSCLC models of anti-PD-1 immunotherapy. Aim 3 will determine whether XRN1 gene expression in human NSCLC tumors may serve as a predictive biomarker for treatment response to anti-PD-1 immunotherapy. The long-term goals of the proposed research are to gain fundamental insights into how RNA metabolism regulates cancer cell survival and anti- tumor immunity and to establish RNA metabolism pathways as potential therapeutic targets in NSCLC. The applicant, Dr. Tao Zou, is an oncologist at Dana-Farber Cancer Institute (DFCI). He spends 80% of his time engaged in research and career development activities and 20% of his time in clinical practice caring for patients with lung cancer. Dr. Zou has outlined a five-year career development plan that will enable him to achieve his goal of leading an independent laboratory that conducts basic and translational research at the intersection of RNA biology and lung cancer immunotherapy. Dr. Zou will perform the proposed research under the mentorship of Dr. Matthew Meyerson, an expert in lung cancer biology with a strong record of training independent investigators in academic cancer research. Together with expert members of Dr. Zou’s Scientific Advisory Committee, Dr. Meyerson will ensure that Dr. Zou will obtain additional training in innate immune RNA sensing, tumor immunology, translational studies using human biospecimens, and computational biology. Dr. Zou will conduct the proposed research primarily at DFCI and will leverage additional resources available to him at the Broad Institute and Harvard Medical School. DFCI is a rich research community with a distinguished track record of training successful physician-scientists. DFCI provides the ideal environment for Dr. Zou to build his research expertise and engage in career development activities prior to transitioning to an independent academic position.

NCI - National Cancer Institute

Project Summary/Abstract Triple-negative breast cancer is an aggressive subtype of breast cancer that tends to metastasize to distant organs early in the course of the disease. Metastasis can occur by cancer cells from the breast tumor directly entering the blood to travel to distant organs (hematogenous metastasis), or by cancer cells spreading from the breast tumor to nearby lymph nodes, and then leaving the lymph nodes to enter the blood and travel to distant organs (lymphatic metastasis). We are interested in understanding how lymphatic metastasis occurs. Cancer cells change their gene expression in order to promote metastasis. One way that cancer cells can regulate gene expression is through the action of noncoding RNAs. We found that the noncoding RNA Snord67 promotes lymphatic metastasis in a mouse model of triple-negative breast cancer. Snord67 is a small nucleolar RNA (snoRNA) that leads to the 2′-O-methylation of another noncoding RNA, U6 small nuclear RNA (snRNA). However, it is unknown whether Snord67 promotes metastasis by increasing the methylation of U6 snRNA or through other, unknown mechanisms. For example, some snoRNAs are known to promote the 2′-O-methylation of protein-coding messenger RNAs (mRNAs), which can lead to changes in mRNA processing, stability, or translation into proteins. The goal of this proposal is to determine whether Snord67 promotes lymphatic metastasis by increasing the methylation of U6 snRNA or by performing other functions, such as increasing the methylation of mRNAs. This proposal includes two aims: (1) Determine the functional importance of Snord67- guided 2′-O-methylation of U6 snRNA at C60 (canonical mechanism) in the promotion of lymphatic metastasis by Snord67, and (2) Determine the contribution of Snord67-guided 2′-O-methylation of target mRNAs (non- canonical mechanism) to the promotion of lymphatic metastasis by Snord67. These studies will help us better understand how triple-negative breast cancer spreads and could potentially lead to new approaches for treating or preventing breast cancer metastasis. The trainee will work in a highly productive multidisciplinary scientific environment and develop proficiency in a variety of experimental methods in RNA biology and cancer biology under the mentorship of physician–scientist experts.

NCI - National Cancer Institute

PROJECT SUMMARY Funds are requested to provide partial support for the inaugural FASEB Science Research Conference (SRC) on biomolecular condensates, titled "Phase Transitions in Cellular Signaling and Disease”, to be held from January 11–15, 2026, in Melbourne, Florida, USA. Biomolecular condensation has been recently discovered to be a ubiquitous phenomenon in living systems, supporting normal physiology and driving disease processes, including cancers and neurological disorders. These discoveries have generated immense interest among biologists, chemists, physicists, engineers, and computer scientists to develop an integrated experimental, theoretical, and computational framework to understand phase transition as a mechanism for programming cellular signaling, stress regulation, and genome organization. Aberrant behaviors of condensates have been shown to result in alterations in soluble protein homeostasis, dysregulation of signaling events in the cytoplasm, and activation of oncogenic transcriptional programs in the nucleus. These discoveries have also fueled new directions in drug discovery research, which are currently pursued by biotech and pharma companies. The 2026 conference on biomolecular condensates will feature two keynote lectures, 30 invited speakers and session chairs, including rising stars, and up to 150 attendees. The specific objectives of the conference are to stimulate and enable: 1) scientific knowledge exchange, both among academic researchers and between academia and industry, 2) professional networking and collaboration, and 3) peer mentoring and support for early-career scientists. Besides keynotes, invited and contributed talks, and poster sessions, the program will include a Career Development Workshop for trainees and junior faculty members to address career choices and milestones in a panel discussion format. It will also feature a Meet-the-Expert/Speaker Session covering a range of professional development topics, fostering an interactive platform for knowledge sharing, peer mentoring, and professional networking. Through these activities, this FASEB conference will catalyze new connections between molecular biophysics, cell and molecular biology, cancer biology, neuroscience, and drug discovery communities, enabling exchanges of cutting-edge discoveries and identification of major challenges as the field moves forward.

NCI - National Cancer Institute

ABSTRACT The second annual RISE UP (Revolutionizing Investigations to StEp Up Prevention) for Breast Cancer conference will bring together practitioners, scientists, and advocates across women’s health specialties and leverage what we know about breast cancer biology, treatment, and hormonal management to better approach breast cancer prevention and treatment. RISE UP was conceptualized in 2023 by Dr. Laura Esserman. The first meeting was held in November 2024 with over 300 attendees across a variety of disciplines. Our goal is to build on the momentum of the first meeting and concentrate on the following aims for 2026: 1) highlight novel and standard agents that can be applied in the context of response-predictive subtypes in the early-stage setting to eradicate tumors; 2) highlight results from personalized screening programs and the opportunity to personalize both risk reduction and screening; 3) explore opportunities to pair breast cancer risk reduction in interventions across a woman’s life stage to both optimize for breast cancer prevention and improve treatments and quality of life for breast cancer survivors. The conference will include general sessions (including debates, keynote speakers, abstract presenters, and panel discussions) as well as poster sessions to foster cross disciplinary learning, highlight new research, and spark ideas and action. General sessions will be designed to educate attendees about opportunities to improve the health and well-being of women from prevention to treatment of breast cancer. Our goal is to bridge the critical gap in knowledge of breast specialists and gynecologists to make breast cancer management better, engage the gynecologic and primary care community in improvements in breast cancer screening and prevention, and to rethink hormonal control across the continuum of a woman’s life with an eye toward prevention. The conference is designed to foster questions, collaborations, and overall generation of new ideas and ways of thinking about breast cancer. There will be no overlapping sessions so that all attendees will gain the knowledge and ability to improve their practice and upend the way we think about breast cancer prevention. The conference will be held February 19- 21, 2026, at the Hotel Nikko in San Francisco. We aim to bring new energy and novel perspectives to the challenge of breast cancer prevention. The final session of the conference will be a “shark tank” like challenge, with a competition to integrate breast cancer risk reduction into health care products used during a woman’s life course. Last year we awarded four “SPARK” awards to foster early-stage ideas and collaborations, and the winners will present during the meeting and report on their progress. We plan to partner with more investors this year to award both SPARK and IMPLEMENTATION (later stage development ideas) prizes.

NCI - National Cancer Institute

SUMMARY The DNA Damage, Mutation, and Cancer Gordon Research Conference (GRC) is a premier international scientific meeting with over 25 years of history, dedicated to exploring the intersection of genomic stability and cancer. This five-day conference showcases cutting-edge, unpublished research on the mechanisms that maintain genome integrity and their roles in oncogenesis and genotoxic cancer therapy. With a strong emphasis on in-depth mechanistic discussions and trainee engagement, the GRC fosters collaboration among researchers at all career stages and disciplines, aiming to translate fundamental discoveries into improved cancer diagnostics and treatments. The scientific program features invited talks from leading researchers across the U.S., Europe, and Asia, an equal number of short talks selected from abstracts, and extended poster sessions to encourage participation at all levels. Key topics include mechanisms of mutagenesis, DNA replication and recombination, chromosomal translocation, and aneuploidy. In response to the growing number of cancer survivors, which are estimated to be nearly one-third of U.S. adults over 65, the 2025 meeting will introduce three emerging themes that address the short- and long-term toxicity of genotoxic cancer therapy: instability in genomic dark matters (damage and rearrangement of repetitive sequences, ribosomal DNA, and mitochondrial DNA); crosstalk between genomic instability and the immune response (both innate and adaptive with implication in chronic inflammatory responses); DNA damage and repair in neurons, crucial for understanding neuropathy from cancer treatments and brain malignancies. These themes will incorporate novel technologies and strategies, providing attendees with the latest perspectives on mitigating genomic instability and enhancing cancer therapies. The conference, held in early spring at a beachside venue in Ventura, California, provides a relaxed setting for both structured and informal networking, including communal meals, afternoon sports, and two dinners with themed tables for scientific exchange and career development discussions. A message board will also be provided to facilitate interactions between students seeking postdoctoral positions and PIs who have open positions. A Power Hour will facilitate conversations on scientific growth in the digital and AI era. To further engage young scientists, a pre-meeting Gordon Research Seminar (GRS) will offer early-career researchers a platform to present and discuss their work. Additionally, session chairs will prioritize the first question after each talk for trainees whenever possible, fostering deeper engagement and participation. By bringing together experts from different disciplines, geographic areas, and career stages, this GRC aims to advance our understanding of genomic instability and its implications for cancer, paving the way for more effective therapies and improved patient outcomes.

NCI - National Cancer Institute

Cold Spring Harbor Laboratory Conference on The PARP Family and ADP-ribosylation March 25 to 28, 2026 ABSTRACT This proposal seeks support for a scientific meeting on “The PARP Family and ADP-ribosylation,” held at Cold Spring Harbor Laboratory (CSHL) on March 25–28, 2026. ADP-ribosylation is a reversible post- translational modification (PTM) of proteins, RNA, and DNA catalyzed by the enzymes of the PARP family— comprising 17 members in humans. PARPs utilize nicotinamide adenine dinucleotide (NAD⁺) as a substrate to transfer either a single ADP-ribose unit (mono-ADP-ribosylation, or MARylation) or multiple units in a chain (poly-ADP-ribosylation, or PARylation). Like other PTMs, ADP-ribosylation involves "writer," "eraser," and "reader" proteins. Initial research focused on the writers PARP1 and PARP2, which generate PAR chains in response to DNA damage, leading to the discovery of the synthetic lethal interaction between PARP1/2 and BRCA1/2 tumor-suppressing genes and the development of four FDA-approved dual PARP1/2 inhibitors for BRCA1/2-deficient cancers (breast, ovarian, pancreatic, and prostate), highlighting the contribution of fundamental discoveries to cancer therapeutics. Recent studies have expanded the functions of PARP1/2 beyond DNA repair and addressed the dose-limiting toxicity of PARP inhibitors in cancer therapy. There is also a growing knowledge of other PARP family members. PARP7 was recently identified in a synergistic lethal screen with histone demethylases mutated in cancer. Notably, > 50% of PARPs, including PARP7, are interferon-inducible. They, including PARP7, PARP11, and PARP14, play critical roles in modulating immune responses in cancer. Several PARP7 inhibitors are in clinical development for cancer therapy, reflecting the growing therapeutic potential of PARP family members beyond PARP1&2. Beyond the writers, recent studies have also expanded to erasers, such as PARG, in RNA ADP-ribosylation dynamics, driven by the development of potent and membrane-permeable selective PARG inhibitors. Marking a significant milestone in the field, PARG inhibitors are the first ADP-ribosylation eraser inhibitors to be evaluated in cancer clinical trials. The unique chemical composition of PAR with both sugar and ribose components renders innovations in chemical biology, structural biology, and mass spectrometry methods critical for studying ADP-ribosylation. This timely and unique meeting will bring together leading experts and emerging investigators to present and discuss cutting-edge research on PARPs and ADP-ribosylation. Sessions will span multiple disciplines, including genetics, chemical biology, and cell biology, and address topics such as DNA repair, immunity, synthetic lethality, and neurotoxicity. Each session will be co-chaired by two prominent scientists. Talks will include invited presentations from established leaders and rising stars and abstracts selected from submitted applications by graduate students, postdoctoral fellows, and junior faculty. We anticipate approximately 180 attendees, with most contributing a talk or poster. This premier meeting will promote innovation and strengthen the global ADP-ribosylation research community by integrating fundamental and translational perspectives and fostering interdisciplinary collaboration between academic and industry scientists.

NCI - National Cancer Institute

Project Summary The 2026 Gordon Research Conference in Single Cell Cancer Biology (GRC-SCCB) is a 7-day conference that will be held March 21-27 at the Four Points Sheraton hotel in Ventura, California. The rapid advancement of single cell technologies has provided an unprecedented opportunity to answer longstanding questions about the impact of intratumor heterogeneity, cellular plasticity, clonal evolution, tumor-stroma interactions, and mechanisms of metastasis and therapeutic resistance. These questions have been difficult to address through characterization of bulk tissue samples, which are limited to providing an average signal from a complex population of cells. cancer, such as The specific aims of the 2026 GRC-SCCB are to 1) present new discoveries in cancer made using single cell approaches, 2) highlight technological and analytic advances for analyzing single cell data, 3) foster cross-disciplinary collaboration to drive new innovation and discovery, 4) promote clinical application of new technologies and discoveries, and 5) provide a forum for the scientific and career development of junior investigators. The meeting will bring together experts in industry and academia, with wide-ranged expertise in cancer biology, imaging, engineering, single cell technologies, computational biology, and clinical oncology to foster new ideas, collaborations, and leadership for the coming decade of rapid progress in in the field of single cell cancer biology.

NCI - National Cancer Institute

PROJECT SUMMARY / ABSTRACT This administrative supplement request seeks continued support for the Early Therapeutics Clinical Trials Network (ETCTN) UM1 North American Star Consortium (NASC), led by the Princess Margaret Cancer Centre (LAO) with partnering Academic Organizations including the Moffitt Cancer Center (MCC), Virginia Commonwealth University (VCU), Northwestern University (NWU), the University of Texas Southwestern (UTSW), the Rutgers Cancer Institute of New Jersey (CINJ), and the Sylvester Comprehensive Cancer Center (SCCC). Due to the delayed publication of the new ETCTN Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) has advised that current UM1 sites may request a 12-month extension with funds to maintain critical clinical research operations. During the extension period, NASC will continue executing early-phase therapeutic clinical trials, supporting patient accrual, ensuring high-quality biospecimen collection for protocol-mandated analyses, and sustaining essential scientific and administrative infrastructure. This supplement will permit uninterrupted operation of ETCTN trials across NASC institutions, ensuring continuity of early-phase drug development efforts that are central to the mission of the ETCTN and aligned with the scientific scope of the parent award.

NCI - National Cancer Institute

Abstract Support is requested for a Keystone Symposia conference entitled “RNA Modifications: Bridging Biological Function and Therapeutic Potential,” organized by Drs. Michaela Frye, Schraga Schwartz, Yunsun Nam and Eckhard Jankowsky, with scientific programming input from Keystone Symposia. The meeting will take place March 9–12, 2026 at Keystone Resort in Keystone, Colorado USA. The rapid growth in RNA modification research has shown that chemical modifications of nucleotides regulate RNA metabolism and influence cell functions. Moreover, the ability of single chemically modified nucleotides to change the electrostatic charge, base pairing and stability of RNA molecules can now be used in clinical applications. This includes creating stable artificial RNA transcripts, such as mRNA vaccines or synthetic small RNA molecules, to increase or decrease the expression of therapeutic proteins. However, our understanding of the human transcriptome remains incomplete because we lack full-length RNA sequences that include all their modifications. This knowledge is crucial, as RNA modifications regulate every stage of gene expression, and their pathways are frequently dysregulated across diverse cancer types. In 2022, the first RNA modification inhibitor entered phase I clinical trials for late-stage cancer patients (ClinicalTrials.gov; NCT05584111), highlighting the translational potential of this field. This Keystone Symposia conference will convene field-leading experts to discuss the multidisciplinary aspects of RNA modification research, providing attendees with a broad overview of state-of-the-art research that is not available in other meetings or workshops centered around RNA. The conference program has been designed to highlight groundbreaking research developments, discuss current challenges and focus on therapeutic opportunities. Importantly, this conference program will explore innovative strategies to target RNA modifications in human diseases like cancer, as well as neurological and metabolic disorders. Cutting-edge therapeutic approaches, with an emphasis on the integration of advanced technologies in cancer research, will be emphasized throughout this meeting. Dynamic scientific sessions coupled with informal networking events will encourage an open exchange of emerging research concepts and directions in the field of RNA modifications and foster new collaborations.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT No changes are being made in this proposed supplement to the stated project summary. With the evolution of the Experimental Therapeutics Clinical Trials Network (ETCTN), the Johns Hopkins Translational Science Team (JHTST) supports 8 Affiliate Organizations (AO) under our Lead Academic Organization (LAO) with the goal to enhance and accelerate our collective contribution to the drug development efforts of the NCI. We have organized a comprehensive and cohesive infrastructure that can conduct high-quality clinical trials evaluating novel anticancer agents, in combinations, in molecularly selected patient populations, or rare tumor sites. Our infrastructure stems from the need to be clinically efficient, regulatory compliant and scientifically rigorous in our approach as we collaborate as network members within the ETCTN. Our infrastructure consists of seven experienced NCI-designated Cancer Centers: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Emory Winship Cancer Institute, Georgetown Lombardi Comprehensive Cancer Center, Sidney Kimmel Cancer Center at Thomas Jefferson University (withdrawn), Memorial Sloan Kettering Cancer Center, University of Virginia Cancer Center, University of Wisconsin Carbone Cancer Center, University of Colorado Denver, University of Maryland Greenbaum Cancer Center, and most recently Wake Forest University. This collection of Centers brings together many unique discovery strengths, diverse patient volumes, and locations both urban and rural. We will focus on 4 specific aims: Aim 1- To lead and maintain a clinical trial consortium that will support cancer clinical trials from Phase 1 initiation through proof-of-activity and foster seamless Phase 2 clinical development of NCI CTEP IND agents; Aim 2- To actively participate and engage disease-focused clinical investigators in the ETCTN by promoting accrual to a range of ETCTN studies led by other LAO/AO members; Aim 3- To incorporate and implement innovative correlative and biological laboratory studies in the context of or as eligibility for participation in early phase clinical studies that enhance our understanding of determinants of toxicity and response that will be used for further definitive practice-changing clinical trial evaluation; and Aim 4- To train the next generation of investigators in drug development. With 9 centers within our consortium, we anticipate no problem in meeting the grant metrics of 100 accruals per year, submitting enough LOI concepts to have 6 new studies approved each year, functioning as a network by having Disease-Focused Clinical Investigators champion ETCTN studies at each site across disease sites, and to provide opportunities to engage and train early career investigators in drug development. We anticipate that our contributions within the ETCTN will impact the clinical care of cancer patients.

NCI - National Cancer Institute

Abstract Support is requested for a Keystone Symposia conference entitled “Cancer Immunotherapy: Basic Mechanism Informing Clinical Applications & Combinations” organized by Drs. Jennifer Guerriero, Thomas Marron, Ira Mellman and Solange Peters, with scientific programming input from Keystone Symposia. The meeting will take place at the Fairmont Le Château Frontenac in Quebec City, Quebec, Canada from March 15–19, 2026. While cancer immunotherapy strategies are highly effective, they target only a few immunoregulatory pathways and benefit a limited subset of patients. Most patients either fail to respond or respond briefly before developing resistance. This Keystone Symposia meeting aims to better understand the mechanisms behind this resistance and discuss the immunotherapeutic strategies under development that will harness alternative immune pathways to improve clinical responses. Conference sessions will highlight emerging approaches to targeting stromal and myeloid cells, insights into tumor recognition by lymphoid lineages, and the use of advanced technologies like spatial imaging and AI to understand the tumor microenvironment. Specifically, this meeting will convene leading cancer immunotherapy experts to review the successes and failures of existing therapies, explore new therapeutic targets within host immunity, and discuss the challenges and potential of combination therapies. These interdisciplinary perspectives will provide insight into future clinical applications of novel approaches and optimal combination therapies to advance strategies designed to eliminate cancers through innovative therapeutic approaches using the immune response.

NCI - National Cancer Institute

Project Summary This proposal seeks partial support the Gordon Research Conference on Autophagy in stress, development and disease, to be held from March 15-20th 2026, in Ventura California, USA. Autophagy is a fundamental cellular homeostatic mechanism affecting normal tissue homeostasis and age-related human diseases such as neurodegeneration and cancer. The overarching aim of this GRC series is to explore the expanding role and regulatory mechanisms of autophagy in both physiological and pathological processes, with a particular focus on its impact on human diseases such as cancer. Notably, differences in autophagy activity have been associated with distinct diseases — elevated autophagy is often observed in cancer, while diminished autophagy is linked to neurodegeneration and aging. Given its central role in these prevalent diseases, understanding the fundamental regulatory mechanisms of autophagy holds promise for the development of novel therapeutic strategies. The long- term goal of this GRC series is to highlight the expanding role and regulation of autophagy in physiological and pathological processes that underlie human diseases, such as cancer. The specific aims of the 2026 GRC meeting will be to convene 30 invited speakers and discussion leaders in key areas of autophagy research along with ~200 participants for a five-day conference. The program will include a keynote session with addresses from world leaders in the field. These will include presentations by internationally recognized experts on autophagy in cancer, autophagy and proteostasis with links to immune evasion in cancer, and mechanisms of autophagy activation. Approximately 16-20 short talks will also be selected from submitted abstracts, and two poster sessions will permit all participants to contribute. The significance of this application is that the GRC on autophagy has become the cornerstone of the yearly series of conferences that critically influence, direct and drive research in the international community of autophagy researchers. GRC meetings bring together a broad group of investigators who are at the forefront of the autophagy research field and provide ample opportunities for junior scientists and trainees to present their work and exchange ideas with leaders in the field, thus nurturing the next generation of autophagy research leaders. The health relatedness of this application is that autophagy directly impacts a wide spectrum of human health and diseases related to cancer, aging, inflammation, and neurodegeneration. The research highlighted by GRC meetings on autophagy will lead to a greater molecular understanding of a critical process and help develop new approaches to treat age-related diseases and improve health-span.

NCI - National Cancer Institute

Summary The Epstein Barr virus is a DNA tumor virus that is associated with human pathologies including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, stomach cancer, nasopharyngeal carcinoma and autoimmune diseases. EBV is particularly problematic in the HIV/AIDS population where EBV associated lymphomas are especially prevalent. While more than 90% of the world’s population carries EBV, the virus typically exists in a “latent” state with little impact on the host. In response to certain stimuli or local microenvironmental cues, however, EBV enters the viral lytic replication program, leading to viral spread both within and between hosts. Despite the known role of viral latency proteins in EBV associated cancers, there are well-established links between elevated lytic replication and the onset of EBV associated cancers. Further, general elevation of EBV lytic replication is observed in the context of HIV co-infection (+ or – ART), likely contributing to the increased susceptibility of HIV infected individuals to EBV associated lymphomas and autoimmune diseases. With minimal genetic content, viruses are highly dependent on host cell resources for their replication and they elicit extensive alterations of host cell metabolic processes to facilitate efficient virus replication. One of the most conserved and well studied virus-host interactions in herpesvirus replication is “host shut off” where virus encoded factors degrade host cell RNAs destined for translation, freeing up translation resources for dedicated production of high amounts of viral structural proteins. Recently, the Glaunsinger lab showed that despite inducing global Pol III activation of host B2 SINE elements, the murine γ-herpesvirus, MHV68, inhibits host Pol II transcription as a second arm of host shut off, further promoting preferential viral protein synthesis. Using EBV reactivation models that facilitate interrogation of transcriptome changes in pure reactivating cell populations, we have gained insights into remarkable and unexpected interactions between EBV and the host cell transcriptome. Unlike MHV68, we found that EBV sustains cell Pol II gene expression at canonical promoters during lytic replication and strikingly, causes transcription at >10,000 new Pol II initiation sites across the cell genome. While the reason for the broad induction of predominantly non-coding Pol II (EBV) or Pol III (MHV68) transcription across host genomes is unclear, it could relate to some role in remodeling nuclear structure or redistribution of nuclear resources. Our studies also revealed that EBV reactivation induces widespread, noncanonical exon skipping, the extent of which surpasses the degree of exon skipping observed upon severe depletion of most spliceosome components. Preliminary analysis of KSHV reactivation similarly revealed widespread induction of exon skipping indicating that splicing disruption is not unique to EBV. Previous studies have shown that exon skipping can cause either nuclear retention or cytoplasmic nucleolytic degradation by the cellular nonsense mediated RNA decay (NMD) pathway; and we show that nearly 50% of exon skipping events observed during reactivation are NMD candidates. We hypothesize that EBV (and KSHV) lytic replication induces extensive non-canonical exon skipping of cell transcripts resulting in either nuclear retention or degradation through the cytoplasmic NMD pathway as a second, new arm of host shut off. While classic host shut off has been studied for many years, how specificity for cell transcripts is achieved has been largely enigmatic. Notably, herpesviral lytic genes exhibit a remarkably consistent feature of being primarily mono-exonic (i.e. unspliced). We hypothesize that splicing derangement is a new arm of host shut off that facilitates selective targeting of spliced cell transcripts to free up resources for high-level production of viral proteins. In this proposal, we will test this hypothesis, we will begin to address the mechanisms through which EBV induces splicing derangement and we will begin to address the consequences of splicing derangement on host and viral gene expression.

NCI - National Cancer Institute

Project Summary (Abstract): Glioblastoma (GB) remains one of the most lethal cancers, characterized by a profoundly immunosuppressive tumor microenvironment (TME) that limits the effectiveness of current immunotherapies. While research has heavily focused on traditional regulators of immune cells, nociceptors—pain-sensing sensory neurons known to regulate immune responses in the periphery—have not been studied in GB, creating a significant gap in our understanding of immune regulation in the disease. Of note, in the cranial region, nociceptors are densely concentrated in the dural layer of the meninges but are absent from the brain parenchyma. This anatomical separation from GB tumors has likely contributed to their historical neglect in GB research, overlooking their potential as critical regulators of anti-tumor immunity. Our preliminary data provide compelling evidence that nociceptors play an active role in GB pathogenesis. In syngeneic orthotopic GB mouse models, we observed heightened activation of dural nociceptors in the presence of tumors, marked by increased production of calcitonin gene-related peptide (CGRP), a neuropeptide with known immunomodulatory functions. Furthermore, cerebrospinal fluid (CSF) from GB-bearing mice promotes pronounced axonal elongation in cultured primary trigeminal nociceptors, indicating that tumor-derived factors can directly modulate these neurons. Strikingly, nociceptor ablation in GB-bearing mice leads to transformative changes: prolonged survival, a shift in the TME from an immune-suppressive ‘cold’ state to an immune-activating ‘hot’ state and enhanced responsiveness to immune checkpoint blockade (ICB) therapy. These findings demonstrate that nociceptors, despite their physical separation from the tumor, can remotely regulate GB progression by modulating the immune landscape. To elucidate the mechanisms underlying nociceptor-mediated immune regulation in GB, we are employing methodologies including ELISAs, in vitro neuronal culture assays, single-nucleus and single-cell RNA sequencing (snRNA-seq, scRNA-seq), multi-dimensional flow cytometry, and survival studies under conditions of immune perturbation. These approaches will elucidate the tumor-derived factors that modulate nociceptors and define the bidirectional interactions between nociceptors and immune cells within the TME, revealing the mechanisms by which these neurons regulate anti-tumor immunity. Beyond advancing fundamental understanding, this work holds significant therapeutic potential. By targeting nociceptor-driven immune regulation, we aim to develop strategies to reverse immune suppression in GB, including repurposing existing nociceptor-targeting therapies to enhance efficacy of immunotherapies. Ultimately, our goal is to uncover new therapeutic avenues for improving survival outcomes in patients with this devastating disease.

NCI - National Cancer Institute

The 2026 Annual Meeting of the American Society for Investigative Pathology (ASIP) will be held May16-19, 2026, at the Caloosa Sound Convention Center located at the Luminary & Co. in Fort Myers, FL. The Annual Meeting of the ASIP (marketed as Pathobiology 2026) provides a unique forum for presentation and sharing of cutting-edge research in experimental and translational pathobiology. The target audience and subject matter for the meeting are diverse, but united by a common focus on mechanisms of disease. Reflecting the interests of the ASIP membership, the four-day scientific program for the 2026 Annual Meeting is comprised of major symposia, award lectures, workshops, guest society symposia, and special sessions covering disease pathogenesis, biomarker development, prevention, diagnosis, and therapeutics, advanced technologies, organ systems, and systems biology. This program contains strong components in cancer pathobiology. Major cancer- related sessions will focus on: (i) emerging technologies and artificial intelligence in unraveling cancer heterogeneity, (ii) pathobiology of obesity, (iii) the polyploidy paradox: whole genome duplication in homeostasis, regeneration, and cancer, (iv) mapping the future of cancer prevention: pre-cancers, atlas insights, and interception strategies, and (vi) circulating biomarkers in breast cancer: liquid biopsy for detection, monitoring therapy, and recurrence. Several other scientific sessions will include talks with a cancer focus. In addition, three meritorious award lectures will have a cancer-specific focus: the Gold-headed Cane Award - Cells and Networks in Flux: Rethinking Ontogenesis and Pathogenesis; the Rous-Whipple Award Lecture - Pros and Cons of Livering Longer; and the Cotran Young Investigator Award - The Lymphatic System in Disease Progression. Most major symposia will include abstract-driven talks by trainees and young investigators. Additional opportunities for presentation of cancer-focused research will include abstract-driven minisymposia and poster discussion sessions, which will intentionally feature young investigators and trainee scientists. The program further provides a number of sessions focused on education and career development. These sessions are designed for trainees and young investigators, but are open to all attendees. The ASIP regards promotion of the career development of trainee and young investigators as an extremely important aspect of the Annual Meeting. Accordingly, the meeting provides not only special events designed for their needs, but also sessions that highlight/showcase their work. The major objectives of this application are to provide an exceptional cancer-focused scientific program during the 2026 Annual Meeting and to promote the participation of trainees and young investigators through provision of a Scholar Award program targeted to graduate students, postdoctoral fellows, clinical residents/fellows, and junior faculty members.

NCI - National Cancer Institute

The mission of the American Society of Preventive Oncology (ASPO) is the exchange of scientific information to reduce the cancer burden and for the continued development of investigators involved in cancer prevention and control. The 50th ASPO Annual Meeting will be held April 12-14, 2026, at the Hilton Denver City Center. This application requests partial support for that meeting, which is a keystone of this multidisciplinary organization. ASPO’s annual meeting provides a high-quality program that fosters new opportunities for early career, mid-career, and senior investigators whose careers are focused on the primary, secondary, and tertiary prevention of cancer. The specific aims of the annual meeting and this conference grant are to: 1) provide multidisciplinary forums for the exchange of scientific information; 2) foster implementation and broaden dissemination of scientific discoveries; and 3) provide exceptional professional development to investigators at any career stage, especially early career investigators, to maximize their potential for success. For the 2026 meeting, we plan to continue with our successful and well-received meeting format, while adding special content to celebrate the 50th anniversary of ASPO’s contributions to cancer prevention and control. We will have two poster sessions, each with different presentations, to allow for increased participation and interaction of our attendees. The Best of ASPO sessions allow for 32 abstracts to be selected for 15-minute oral presentations. Our “Looking Back, Thinking Forward” sessions include a 15-minute presentation by a senior investigator on a topic of interest, followed by three short presentations selected from submitted abstracts, as well as time for questions/discussion. The meeting has four symposia, a keynote presentation, two award lectures, four to six Special Interest Group breakfast sessions, and a networking lunch. The committee has worked diligently to include community scientists throughout the programmed sessions. Pre-meeting workshops include multiple professional development sessions, a meeting of cancer center Associate Directors and Program Leaders for Cancer Prevention and Control, and a meeting for NCI training grant directors. ASPO continues its commitment to the development of early career scientists through an expanded New Investigator Workshop. Meeting planning takes satisfaction surveys from previous meetings into account. Abstracts will be solicited beginning in August 2025. Over 175 posters are anticipated to be presented. Multiple initiatives including this conference grant—which requests travel support for early-career and community scientists—enhance the ability for meeting attendees, program committee members, and invited speakers to represent multiple disciplines in cancer prevention and control research and the fields concerned with translating evidence into effective prevention and control programs. All meetings are held in non-smoking, ADA accessible conference facilities. Journal and online advertisements, email, and direct mail will publicize the meeting. Over 450 participants are expected to attend. By fostering communication among multidisciplinary professionals, ASPO meetings have been extraordinarily successful at reaching the society’s goals of supporting mentoring, encouraging dialogue, and promoting innovation.

NCI - National Cancer Institute

PROJECT SUMMARY Immunotherapies targeting adaptive immune checkpoints have improved cancer outcomes, but innate immune checkpoints also play crucial roles in cancer immune evasion and are promising targets for immunotherapy. The innate immune system uses "eat-me" and "don’t-eat-me" signals to regulate phagocytosis, essential for maintaining tissue homeostasis and preventing cancer. Phagocytic cells have also recently emerged as new key actors in the success of immunologically mismatched allograft transplants through human leucocyte antigens (HLA) allorecognition. Thus, identifying the molecular patterns and receptors governing phagocytosis is vital for understanding cancer clearance and transplantation. Recently published studies of the PI revealed novel functions for Vascular Cell Adhesion Molecule-1 (VCAM1) on healthy and malignant hematopoietic stem cells (HSCs). We have found that VCAM1 is highly expressed on healthy HSCs, serving as an innate immune checkpoint for entry into the bone marrow by providing a "don't-eat-me" signal in the context of major histocompatibility complex (MHC) class-I presentation. In addition, we found that leukemia cells exploit this tolerance mechanism to avoid innate immune recognition, suggesting that the VCAM1-receptor axis is a promising target for immunotherapy. However, the specific receptor mediating this interaction remains unknown. In preliminary studies, we employed proteomics and AlphaFold modeling to identify novel VCAM1 receptor candidates on phagocytic cells. Our Specific Aim 1 focuses on identifying the VCAM1 receptor promoting immune tolerance and leukemia evasion and validating its function in vitro and in vivo using mouse and human models of leukemia. Specific Aim 2 will assess the impact of inhibiting or deleting VCAM1 receptor signaling on myeloid and lymphoid leukemia cell clearance, as well as allogeneic transplantation outcomes. Successful completion of this research will advance knowledge of innate immune recognition mechanisms, identify new leukemia immunotherapy targets, and improve outcomes in stem cell transplantation. 1

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT This conference grant application requests funds to help support the Gordon Research Conference (GRC) on Nasopharyngeal carcinoma (NPC) May 10 - 15, 2026. NPC is a deadly cancer arising in the nasopharynx which has high incidence in particular regions, including Alaska. The peak age at NPC diagnosis is in the mid-forties, which is two decades earlier than for many other common cancers. Thus, NPC has a significant socioeconomic impact globally. The etiology of this unique cancer includes three significant co-factors: host genetics, Epstein- Barr Virus (EBV) infection, and environmental influences. How these factors contribute to NPC development is the research focus of numerous labs worldwide. Because of its proclivity for early lymphatic spread, NPC is often diagnosed at an advanced stage, when the cancer is harder to cure and requires aggressive treatment. An enhanced understanding in regard to how EBV and aberrations in cell signaling drive normal cells to become cancerous, how these cells escape from the immune surveillance, and their molecular signatures for early diagnosis as well as for development of novel targeted and immune therapy is expected to improve NPC treatment and outcomes. The fact that the development of NPC requires the convergence of many different factors, including Epstein-Barr infection, host genetics, impaired anti-tumor host immune function, and epidemiological factors, makes this unique cancer a powerful model to dissect out the host-virus-environment interactions, thereby yielding insights into tumor pathogenesis. Studying NPC provides opportunities to address contemporary issues in cancer research (for example, tumor microenvironment, tumor immune surveillance, stem cells, epigenetics, cancer vaccine and immunotherapy). We hypothesize that the 2026 meeting, by featuring cutting-edge NPC basic, translational and clinical research, will provide a unique forum for idea exchange among scientists, clinicians, and industry representatives to catalyze the translation of recent advances into patient care. We will address this hypothesis via three specific aims: 1) To advance knowledge of key NPC basic pathogenetic mechanisms and translational research. 2) To highlight recent advances in nasopharyngeal carcinoma diagnosis and treatment. 3) To provide a stimulating forum that strengthens interactions between basic scientists, translational researchers and physicians and also between junior and senior members of the NPC field. We believe that the scientific environment created at the 2026 NPC Gordon Research Conference meeting will help to advance NPC research and to improve NPC patient care.

NCI - National Cancer Institute

RESEARCH ABSTRACT Cancer Grand Challenges Connecting DNA Adducts, Unexplained Mutational Signatures, and Cancer Etiologies (CAUSE) Host Institution: University of California, San Diego Background: Genome sequencing of thousands of cancers has identified over 100 distinct mutational signatures—recurring patterns of somatic mutations that reflect mutagenic processes. While some have known causes, most—including key cancer-driving signatures—remain unexplained. These include endogenous ubiquitous age-associated signatures (e.g., SBS5), tissue-specific processes (e.g., SBS40), and geography-associated patterns likely linked to unknown environmental exposures (e.g., SBS12, SBS89). Biochemically, most somatic mutations arise from misrepair or replication across damaged DNA (i.e., DNA adducts). Cells experience tens of thousands of DNA adducts daily—from both endogenous metabolism and environmental exposures. While most are accurately repaired, some persist leading to permanent changes in the DNA sequence (i.e., somatic mutations). As a result, cancer genomes preserve a durable, but mechanistically obscured, record of genotoxic damage. Understanding the origins of unexplained mutational signatures requires identifying the initiating DNA adducts and dissecting how their formation, persistence, and processing shape mutational patterns. Aims: The Connecting Adducts, Unexplained Signatures, and Cancer Etiologies (CAUSE) project aims to mechanistically understand unexplained mutational signatures by systematically identifying specific DNA adducts and linking them to the mutations they generate. CAUSE will build a high-throughput discovery platform that integrates chemistry, biology, genomics and cutting-edge technologies. The project will focus on three mutagenic contexts: (1) endogenous processes underlying signatures like SBS5 and SBS40, (2) likely environmental exposures driving tissue- and geography-specific patterns like SBS12 and SBS89, and (3) chemotherapy-induced DNA adducts, which will be used as a controlled benchmark. The proposed approaches are broadly applicable and will help uncover the origins of many unexplained mutational signatures while advancing next-generation mutagenesis technologies such as a reimagined Ames test. Methods: CAUSE will integrate human tissue analysis with diverse experimental systems—including in vitro assays, cell lines, and mouse models—across seven coordinated modules: (1) mass spectrometry to detect diverse DNA adducts; (2) structural characterization via chemical synthesis and microcrystal electron diffraction; (3) genome-wide lesion mapping using Endo-seq, long-read sequencing, and polymerase-stalling enrichment; (4) single-molecule reporter assays of misrepair in defined repair contexts; (5) biochemical perturbations in Xenopus cell-free systems to dissect repair mechanisms; (6) genetic perturbations in animal models to dissect damage and repair pathways; and (7) interpretable AI to model how lesion features and repair status predict mutational outcomes. Impact: CAUSE will generate the first mechanistic atlas linking DNA adducts to mutational signatures. This foundational resource will enable causal attribution, clarify age- and exposure-related mutagenesis, and shift mutational signature research from observational to actionable—transforming cancer prevention, diagnosis, and care.

NCI - National Cancer Institute

RESEARCH ABSTRACT BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death and increasingly affects young adults. Our team has recently made paradigm-shifting discoveries in CRC oncology, biology and signalling, while also establishing proof-of-concept for therapeutic reprogramming and hyperactivation-induced lethality, pioneered the development of the first direct oncogene activator and novel receptor-targeting strategies, with extensive expertise in translating basic research into drug development. Our proposal now unites two key concepts under a single cancer rewiring project: 1) Hyperactivation - Emerging data suggest that many cancer cells are susceptible not only to inhibition of oncogenic signaling - but also overactivation of these same pathways. In CRC the three major signaling pathways that are dysregulated (WNT, MAPK and PI3K) all show evidence for this ‘Goldilocks’ (‘just right’) phenomenon. Moreover, emerging preclinical candidate therapeutics are poised to, for the first time, exploit these newfound vulnerabilities. 2) Cell-state Rewiring - CRC is also notable for the diverse sets of cell-states that drastically modulate the response to clinical therapeutics and likely will influence both response to chemotherapy, targeted pathway inhibition and pathway activators. We are similarly poised to rewire these states to enhance the response to existing and emerging therapies. AIM: Develop clinically tractable strategies using signalling activators and inhibitors to destroy cancer cells via hyperactivation and rewire cancer cells towards vulnerable cell-states. APPROACH: REWIRE-CAN (Reprogramming Epithelial WIRing to Eradicate CANcer) will address this Cancer Grand Challenge by: - DISCOVERING novel agents to modulate and hyperactivate oncogenic pathways (WP1) - DEVELOPING approaches to use novel signalling activators to treat cancer via signalling hyperactivation and cell-state rewiring (WP2) - TRANSLATING therapeutic rewiring strategies into preclinical and clinical proof-of-concept studies (WP3) METHODS: REWIRE-CAN will combine functional analysis of patient samples with advanced drug discovery, including functional genetic screens, clinical bio-specimens, patient-derived organoids, animal models, and custom single-cell signalling technologies. This integrated approach will define combinatorial signalling dependencies in human CRC and allow us to directly translate these findings into in vivo therapeutic studies prior to clinical application. IMPACT: REWIRE-CAN will harness novel signal activators and the unique signalling biology of CRC to create a roadmap for sensitising cancer cells to therapy through signalling rewiring. Our lasting impact will be to identify novel therapeutics for advanced CRC, supported by in vivo proof- of-concept and tractability towards clinical candidate development. REWIRE-CAN will develop much- needed new therapies for CRC and also act as an exemplar for emerging signalling activator therapy in cancer.