Targeted Therapy, Treatment Disparity Featured at Cancer Meeting

UCSF experts highlight leadership in innovative cancer research and education.

| | April 23, 2024

Cells in Lymph Node

Leading cancer researchers from UC San Francisco presented talks about advances in targeted therapy, cancer genomics, eliminating treatment disparities and other cancer research topics at this year’s annual meeting of the American Association for Cancer Research (AACR) conference, which was held April 5-10 in San Diego.   The theme of this year’s conference, “Inspiring Science, Fueling Progress, Revolutionizing Care,” showcased 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 today.     This year’s program featured innovative research and discussions by many experts from the UCSF Helen Diller Family Comprehensive Cancer Center.   Alexander Marson, MD, PhD, UCSF professor of Medicine and director of the Gladstone-UCSF Institute of Genomic Immunology, presented “Decoding and reprogramming T cell circuits with CRISPR” at the presidential select symposium, “Cancer Immunotherapy – Where Do We Go from Here?” Marson discussed the power of using of an emerging set of genomic tools to test every genetic sequence in the genome and write new synthetic genetic sequences to program immune cells to be effective and safe, searching out cancer cells and eliminating them from the body. He also discussed the need to create an interdisciplinary community to bring together different disciplines to unlock the true promise of immunotherapies and produce innovations that will make cancer immunotherapy reach the patients who still desperately need it.   Denise Wolf, PhD, UCSF Department of Laboratory Medicine, was the presenter for “Immune subtyping identifies a subset of HR+HER2- early-stage breast cancer patients with a very high likelihood of response to neoadjuvant immunotherapy (IO): Results from 5 IO arms of the I-SPY2 TRIAL” during the mini-symposium, “Biomarkers Predictive of Therapeutic Benefit.” Wolf reported on the performance of ImPrint (an immune-related biomarker) in HR+HER2- patients from five immuno-oncology (IO) arms from I-SPY2.2 breast cancer trial. The results showed that patients with ER+/HER2-/ImPrint+ breast cancer have a very high probability of achieving complete response to neoadjuvant immunotherapy, while those who are ER+/HER2-/ImPrint- have a low probability of responding. As Wolf noted, “Patient selection based on ImPrint class can result in high response rates and spare non-responders the toxicities of immunotherapy.”   Alejandro Sweet-Cordero, MD, UCSF chief of Pediatric Oncology, presented “Identification of novel osteosarcoma subtypes based on epigenetic and genomic analysis” during the major symposium, “Advances in Pediatric Cancer: Mechanisms, Vulnerabilities, and Translation.” While osteosarcoma is a disease characterized by extreme genomic complexity, Sweet-Cordero and his team hypothesized that this disease could have subtypes that could be identified through the lens of epigenetics. They used epigenetic analysis approaches to evaluate changes to the chromatin (a mixture of DNA and proteins that form the chromosomes) organization of osteosarcoma. They found that these tumors have two distinct subtypes and that these subtypes may have specific vulnerabilities to different drugs that are being tested in preclinical models.

Kevin M. Shokat, PhD, UCSF professor of Cellular and Molecular Pharmacology and AACR Academy Fellow, served as chair and presented “Expanding K-Ras covalent chemistry for targeting K-Ras (G12D)” during the Advances in Diagnostics and Therapeutics session, “KRAS: Broadening the Attack Beyond G12C with Small Molecules and Immuno-oncology.” While KRAS mutations were a shining example of undruggable cancer targets for decades following their discovery in the early 1980s, the KRAS-G12C inhibitors sotorasib and adagrasib broke a 40-year drought in targeted treatment. While G12C mutations are very prevalent in lung tumors, G12D is the most common KRAS mutation in pancreatic ductal adenocarcinoma, as well as colorectal, non-small cell lung, and other cancers, and is much harder to target than G12C. Shokat explored the latest findings in KRAS chemistry and structure in the continuing search for novel small molecules that target G12D mutations.    Darwin Kwok, MS, cancer immunotherapy PhD candidate at UCSF, presented “Novel public and tumor-wide neoantigens arising from clonal aberrant splicing events drive tumor-specific T-cell responses across diverse cancer types” during the mini-symposium, “Novel Molecular Targets and Biomarkers.” Kwok discussed his glioma study that included development of a novel computer model for detecting tumor-specific splicing events (neojunctions) across multiple cancer types. He discussed how the research successfully identified a new class of spliced neoantigens (a class of tumor-specific antigens) that elicit T- cell-mediated immune responses. Kwok noted that research may offer an off-the-shelf immunotherapy approach that tackles the critical challenge of intratumor heterogeneity (a driver of tumor development) in immunotherapy resistance.    Matthew Krummel, PhD, professor of Pathology and Robert E. Smith Endowed Chair in Experimental Pathology at UCSF, presented “Using archetypes and machine learning to discover novel immune pathways for tumor elimination” during the major symposium, “Discovering and Broadening the Therapeutic Modalities of Immune Therapy.” Krummel was among the presenters focusing on novel and investigative modalities for improving immune therapy. His discussion looked at using immune archetypes across different tumor microenvironments and machine learning to uncover new approaches for tumor elimination.    June Chan, ScD, the Steven and Christine Burd-Safeway Distinguished Professor of Epidemiology and Biostatistics at UCSF, served as chair for the major symposium “Health Behavior Practices After Cancer Diagnosis to Deter Cancer Progression and Death: Evidence, Gaps, and Solutions,” and presented “Does exercise or fitness deter cancer progression after diagnosis?” She discussed how evidence is growing that diet and physical activity after a diagnosis of cancer deters cancer-specific and death related to any cause. She reviewed the likely biological mechanisms for which exercise provides benefit for cancer survival. She also discussed the need for innovative solutions to increase nutritional quality and exercise in cancer survivors, in particular among those who are historically under served and/or of lower socioeconomic status.   Hope Rugo, MD, a medical oncologist, Winterhof Family Endowed Professor in Breast Cancer, and director of Breast Oncology Trials and Clinical Education at UCSF, was a non-affiliated discussant for two UK trials called the Partner trials. She spoke during the clinical trials plenary session, “Advances in Targeted Therapy,” reviewing the results of the trials which explored the impact of “gap scheduling” in order to add a PARP inhibitor to chemotherapy in the safest and most effective manner to improve neoadjuvant response to treatment for patients with early-stage breast cancer. Her talk examined the impact of the gap scheduling on patients who had germline BRCA mutations in contrast to patients who had triple negative breast cancer and were treated in the neo-adjuvant setting. She noted, “This study was small and closed with less than half the number of patients researchers had planned to enroll, which may have affected the researchers’ ability to assess other characteristics affecting treatment outcomes or causing toxicities.”    Scarlett Gomez, PhD, MPH, an epidemiologist and UCSF professor of Epidemiology and Biostatistics, served as chair for the major symposium, “Socioeconomic Contributions to Cancer Health Disparities” and also presented “Multi-level socioeconomic contributions to cancer health disparities from concept to measurement to practice.” The session reviewed current frameworks for conceptualizing and measuring the impacts of social and socioeconomic factors at multiple levels, as well as the research examining these factors in adolescent and young adult and in adult cancer patients. The session also addressed solutions for intervening upon social and socioeconomic disparities.   Jennifer Ruben Grandis, MD, an otolaryngologist and associate vice chancellor for clinical and translational research at UCSF, led a “meet the expert session” on “Identifying and Measuring Gender Inequities in Science and Medicine.” She discussed the findings of a qualitative research study she conducted using in-depth, in-person interviews with 54 women and 54 men who were medical school faculty members at 16 institutions across the United States. The study’s goal was to better understand why women scientists experience higher rates of discrimination based on sex. In the session, she explored the institutional metrics that should be evaluated to identify, track, and assess potential interventions designed to mitigate inequities.    Boris Bastian, MD, PhD, a dermatologist and the Gerson and Barbara Bass Bakar Distinguished Professor in Cancer Research at UCSF, presented “When you come to a fork in the road, take it: Navigating the diverse evolutionary paths from precursor lesions to melanomas” during the Advances in Prevention Research session, “From Precursors to Prevention: How Research into Cancer Precursor Lesions Creates Prevention Opportunities.” Bastian described different melanoma subtypes and their evolutionary trajectories from different families of precursor lesions. The varying sequential order in which specific mutations become selected between these ‘pathways’ indicates unappreciated differences in which tumor suppressive mechanisms are engaged and how they are phased during tumor evolution. He noted these differences likely indicate variations in the respective cell of origin, their differentiation, and their functional stage, determining specific vulnerabilities along which tumor evolution can occur.