Leading cancer researchers from UC San Francisco presented talks about advances in targeted therapies, cancer genomics, using AI to personalize cancer treatment, improving diagnosis of hard-to-treat cancers and other cancer research topics at this year’s annual meeting of the American Association for Cancer Research (AACR) conference, held April 25-30 in Chicago.
The theme of this year’s conference, “Unifying Cancer Science and Medicine: A Continuum of Innovation for Impact,” highlighted the latest advances in the biology, prevention, detection, diagnosis and treatment of cancer, as well as state-of-the-art concepts and technologies shaping cancer research.
This year’s program featured innovative research and discussions by many experts from the UCSF Helen Diller Family Comprehensive Cancer Center.
Plenary Sessions and Symposia:
Opening Plenary Session PL02 – Opening Plenary: Unifying Cancer Science and Medicine – A Continuum of Innovation for Impact
Kevan M. Shokat, PhD, UCSF professor of Cellular and Molecular Pharmacology and AACR Academy Fellow, presented “Overcoming the Undruggable Nature of the Most Common Human Oncogene, K-Ras.” Somatic mutations in the small GTPase K-Ras are responsible for approximately 30% of human cancers and are generally associated with poor response to standard therapies. The mutations in K-Ras were identified in the early 1980s but it took almost four decades for the first drugs targeting the protein to be approved. The long delay was a result of the apparent lack of a drug binding pocket on K-Ras despite detailed structural and biochemical characterization of the protein, leading to it being referred to as “undruggable.” While progress has been made with new medicines, such as sotorasib and adagrasib, being approved for patients with K-Ras (G12C) lung cancer, drug development of agents to inhibit the more frequent K-Ras (G12D) and K-Ras (G12V) versions found in colon and pancreatic cancer still remain a challenge. Another challenge is drug resistance, which is faced by all targeted cancer therapies including the new K-Ras (G12C) directed drugs. In this lecture Shokat provided perspective on challenges and opportunities of newly developed K-Ras targeting drugs.
Plenary Session PL04 – Targeting the Cancer Ecosystem
Max F. Krummel, PhD, Robert E. Smith Endowed Chair in Experimental Pathology at UCSF, presents “Leveraging Tumor Immune Archetypes in Treating Cancer.” The immunotherapies have transformed cancer cures, resulting in nearly 50% cure rates in deadly diseases such as melanoma. Why these patients benefit but many others with cancers do not has been a mystery for the nearly 30 years since these drugs were first developed. As a result of a large collaborative project based out of UCSF, Krummel and his team have now found clear patterns of how the immune system is set up across thousands of tumors. These patterns are called immune archetypes, and they subdivide patients, not by their type of cancer but by the immune system’s initial state in their tumor. Krummel’s team collected data from the past five years that demonstrates how the nature of the immune archetype is a critical feature for the 50% of the patients who respond to immunotherapies. The research also shows how these archetypes provide unique but now addressable challenges as strategies are implemented to cure the rest of cancers. Krummel presented examples of initial “nudge drugs” that push the immune system into new states with early data for these being soon applicable to patients.
Major Symposium SY05 - Cardio-Oncology: A Novel Platform for Investigation
Javid Moslehi, MD, William Grossman Distinguished Professor in Cardiology and chief of the UCSF Cardio-Oncology and Immunology Program, was chairperson of the session and presented the talk “Immune Checkpoint Inhibitors and Cardiac Toxicity: From Mice to Humans.” In the past 20 years, cardio-oncology has emerged as a new cardiovascular subspecialty in part because of the success that has been attained in oncology. Patients now live longer with cancer, making cardiovascular health more relevant. Although these therapies have changed the natural course of many cancers, several may also lead to cardiovascular complications. Many new anticancer drugs approved over the past decade are “targeted” therapies that interfere with intracellular signaling contributing to tumor progression. Unexpected cardiovascular and cardiometabolic effects of patient treatment with these inhibitors have provided unique insights into the role of these targets in human cardiovascular biology. Moslehi proposed that numerous ongoing oncology clinical trials are an opportunity for closer collaboration between cardiologists and oncologists to study the cardiovascular and cardiometabolic changes caused by the modulation of these pathways in patients. They can serve as a potential avenue for optimization of anti-cancer therapies and for cardiovascular research and drug discovery.
Major Symposium SY08 - Developments in RAS Signaling Inhibition: Bench to Bedside
Frank McCormick, PhD, FRS, the David A. Wood Chair of Tumor Biology and Cancer Research and professor in the UCSF Department of Cellular and Molecular Pharmacology, was chairperson for the session and also presented “The End of KRAS Cancers?” McCormick provided an overview of some of the approaches that he and others are taking to attack cancers driven by mutant KRAS and reviewed some of the drugs developed that use different mechanisms to attack this protein. He talked about new approaches being employed to further increase the chances of treating these cancers.
Major Symposium SY16 – Novel Classes of Human Cancer Rejection Antigens: Beyond Point Mutations
Hideho Okada, MD, PhD, director of the UCSF Brain Tumor Immunotherapy Center and UCSF professor of Neurological Surgery, Surgery and Immunology, presented “Tumor-Wide RNA Splicing Aberrations Generate Therapeutically Actionable Public Neoantigens.” T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens. However, their efficacy is limited in tumors with few somatic mutations and substantial intratumoral heterogeneity. In this presentation, Okada discussed novel sources of antigens for cancer immunotherapy, including a previously uncharacterized class of tumor-wide public neoantigens originating from RNA splicing aberrations in diverse cancer types. He and his team identified T cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22. In cases with multi-site biopsies, they detected the tumor-wide expression of the GNAS neojunction in glioma, mesothelioma, prostate cancer and liver cancer. Their study highlights a role for dysregulated splicing factor expression in specific cancer types and their findings establish a molecular basis for T cell-based immunotherapies addressing the challenges of intratumoral heterogeneity.
Major Symposium SY26 – Metabolism and Organelle Biology in Cancer
Rushika Perera, PhD, vice chair of the UCSF Department of Anatomy and chief scientific officer of the UCSF Pancreas Center, was chairperson for the session and presenter of “Decoding Novel Lysosome Functions in Pancreatic Cancer.” Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive cancer of the pancreas. PDAC tumors are highly reliant on nutrient-scavenging pathways, such as autophagy, and the lysosome to sustain metabolic homeostasis and cellular quality control. To fully understand the functions of the lysosome in PDAC progression, Perera’s lab uses biochemical approaches to isolate intact lysosomes from PDAC cells, followed by mass spectrometry-based proteomics. Using this strategy, the research team has uncovered unique features and functions of PDAC lysosomes that promote cellular adaptation to stress and tumor growth. They have developed techniques to profile lysosome content and composition during different stages of tumor evolution including metastasis to the liver and lungs – the two major sites of secondary tumor growth in PDAC patients. This research highlights how dynamic changes in lysosome composition in vivo enables PDAC cells to rapidly adapt to growth at different organ sites and may inform the development of therapeutic strategies focused on lysosome inhibition in cancer.
Major Symposium SY42 – Tissue Mechanics and Physical Forces in Cancer
Valerie M. Weaver, PhD, director of the UCSF Center for Bioengineering and Tissue Regeneration and professor of Surgery in the Division of Surgical Oncology, presented “Forcing Cancer Initiation and Progression Through Myeloid Lipid Peroxidation-Mediated DNA Damage” during which she discussed cancer as a physical disease and how the interplay between connective tissue, physical forces and immune response plays a role in cancer risk, cancer aggression and therapy response. She reviewed how the immune system spurs the fibrosis and mechanical changes in tissues that drive cancer and how the immune cells respond to the altered physical properties of that connective tissue, corrupting their anti-tumor response and metabolism. In addition to changing the metabolism, the extracellular matrix and anti-tumor function, myeloid cells produce lipid aldehydes that cause DNA damage and mutations in the cancer tissue. She examined ways to correct the behavior of corrupted myeloid cells including development of novel treatments.
Major Symposium SY49 – Minorities in Cancer Research Scientific Symposium: Using Self-identified Race/Ethnic Categories in Cancer Disparities Research in the Era of Precision Medicine
Scarlett Lin Gomez, MPH, PhD, co-leader of the UCSF Cancer Control Program and professor in the UCSF Department of Epidemiology and Biostatistics, presented “Minorities in Cancer Research Scientific Symposium: Using Self-identified Race/Ethnic Categories in Cancer Disparities Research in the Era of Precision Medicine.” Over the past 25-years, the science of cancer health disparities research has evolved from first-generation studies that focused on describing population group differences in cancer incidence and mortality to transdisciplinary translational studies that investigate the contribution of biological, behavioral, clinical and social drivers to cancer care outcomes. Gomez discussed how the research should be moving towards analytically striking a balance between disaggregation and statistical stability and whether it is possible to achieve both.
Gomez also presented “Prevention, Early Detection, Population Sciences, and Disparities Research” during Plenary Session PL06 – AACR Annual Meeting 2025 Highlights: Vision for the Future. She was one of three speakers giving a summary wrap-up of the highlights and themes from the conference. Specifically, she covered presentations in the areas of prevention, early detection, population sciences and disparities.
Mini-symposium MS.ET02.01 – Novel Cancer Therapeutic Targets
Tadashi Manabe, MD, PhD, UCSF post-doctoral scholar, presented “Unveiling the Potent Anti-Tumor Activity and Underlying Mechanism of Action of the Novel Pan-RAF Inhibitor Exarafenib in BRAF-Mutated NSCLC” (#6389). This research investigated the anti-tumor activity and mechanism of action of exarafenib, a novel pan-RAF inhibitor, in BRAF-mutated NSCLC. Analysis of the GuardantINFORM database revealed that 65% of BRAF-positive NSCLC patients harbor Class II and III mutations, with Class II showing significantly poorer prognosis. Exarafenib demonstrated potent activity against all BRAF classes in preclinical models, including cell-free assays, cell lines and in vivo models. Manabe and the research team identified RAS activation as the primary resistance mechanism through Western blot analysis and validated this through RAS knockdown studies and pharmacological approaches. MEK and ERK inhibitor combinations showed strong synergy with exarafenib, confirming RAS-driven MAPK pathway activation as the specific resistance mechanism. Initial clinical data from the ongoing KN-8701 trial (NCT04913285) has shown promising responses in patients with Class II BRAF alterations, providing rationale for further clinical evaluation in this underserved population.
Major Symposium SY29 – Biomolecular Condensates in Cancer: Mechanisms and Therapeutic Opportunities
Xiaokun Shu, PhD, professor in the UCSF Department of Pharmaceutical Chemistry, presented “New Physical Biology of Oncoprotein Condensates: Differential Regulation of the Transcriptome by Phase Separation.” Myc is an oncoprotein transcription factor that is dysregulated in over half of all human cancers. Dysregulation results in unbalanced Myc activity and leads to tumor development. The molecular mechanism of how mixed dysregulation results in tumorigenesis is still unclear despite more than three decades of research, and there is still no FDA-approved drug against Myc. The goal of the researchers has been to develop a therapy for Myc-induced cancer that results from dysregulation and unbalanced power of Myc. Shu reported on the development of a protein-protein interaction reporter to screen a large number of small molecules, identifying potent molecules that are now being testing in animal models.
Mini-symposium MS.CL01.01 – Liquid Biopsy: Circulating Tumor Cells
Laura Huppert, MD, a breast oncologist and assistant professor in the UCSF Division of Hematology/Oncology, presented “Development of a Novel Assay to Detect Circulating Tumor Cells (CTC) in the Cerebrospinal Fluid of Patients With Leptomeningeal Disease” (#1147). Approximately 5% to 15% of patients with metastatic breast cancer (MBC) will develop leptomeningeal disease (LMD), characterized by the spread of tumor cells to the lining of the brain and spinal cord. Diagnosis can be limited by the availability to detect tumor cells in the cerebrospinal fluid (CSF) and prognosis of LMD is poor – on the order of less than six months – with limited treatment options. Given the poor prognosis after diagnosis of LMD, improving methods to detect rare CTCs in the CSF could lead to earlier intervention and improved patient outcomes. To address this unmet clinical need, the researchers developed a novel process for detecting and characterizing CTCs in the CSF of patients with LMD. Testing in model systems demonstrated capabilities for detecting and biomarker expression analysis in rare model CTCs. Pending the method’s clinical validation using patient samples, Huppert and the research team aim to detect and isolate individual CTCs for downstream molecular characterization. This platform could increase the sensitivity of LMD diagnosis, which has the potential for a positive impact on patient outcomes.
Town Meeting: Session TM07 – Charting the Trajectory for Advancements in Pediatric Cancer Research- A Pediatric Cancer Working Group Town Hall
Alejandro Sweet-Cordero, MD, UCSF chief of Pediatric Oncology and chair of the AACR Pediatric Cancer Working Group, hosted the 2025 PCWG Town Hall, which featured presentations from experts in the pediatric cancer community on the theme of “Charting the Trajectory for Advancements in Pediatric Cancer Research," followed by a panel discussion. He also served as chairperson and presenter for the Major Symposium DC07 - Molecular Tumor Profiling for Pediatric Oncology.
Methods and Education Sessions:
Methods Workshop – Session MW02 – Application of AI and Natural Language Processing to Advance Cancer Research and Treatment
Travis Zack, MD, PhD, oncologist and UCSF assistant professor of Medicine, presented “Utilization of Language Models for Medical Information Retrieval.” Zack discussed the use of AI and large language models (LLM) for clinical research in oncology. When it comes to treating patients in cancer, much of the most important treatment data exists within physician notes. This kind of data can be difficult to understand, both on an individual level and at scale. Zack’s research endeavors to use that data to create predictive models to better inform cancer care on a personalized level. He discussed how to find the best ways to optimize LLM use when it comes to clinical documentation, as well as the limitations of these tools. He also provided an example of their power by looking at adverse events across the entire cancer center to better understand the personal experience of each patient and then predict the right trajectory for each patient using that information in AI models.
Education Session ED44 – Theranostics: The Nuts and Bolts
Robert Flavell, MD, PhD, a radiologist and chief of Molecular Imaging and Therapeutics in UCSF Department of Radiology and Biomedical Imaging, presented “Evolving Role of Translational and Clinical Theranostics.” Flavell presented preliminary results from PET Imaging Study of 89Zr-DFO-YS5 in men with prostate cancer and metastatic castration-resistant prostate cancer and also discussed theranostics – harnessing the same molecular pathway for imaging and therapy, and the modular design of enabling labeling of targeting molecule with imaging radionuclide or therapy. He touched on the latest developments in radioactive iodine; prostate cancer-pre-chemotherapy approval of Lutetium-177 PSMA (Pluvicto); ongoing clinical trials in PSMA theranostics; and evaluation of new targets beyond PSMA in prostate cancer theranostics, including antigen CD46.