Advances in targeted therapy, cancer genomics and eliminating treatment disparities were among the topics that were presented by leading cancer researchers from UC San Francisco at this year’s annual meeting of the American Association for Cancer Research (AACR) conference, 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. The gathering brought together scientists, clinicians, health care professionals, survivors, and patients.

This year’s program featured innovative research and discussions by many experts from the UCSF Helen Diller Family Comprehensive Cancer Center. Here are some highlights:

Leading UCSF Presentations (All times Pacific):

3:00 p.m. – 4:30 p.m. | Measuring Structural and Social Determinants of Health in Cancer Research

, PhD, MPH, a social and behavioral scientist and UCSF associate adjunct professor, served as chairperson of this session and also presented “

Characterizing social and built environments in cancer epidemiology cohorts: Geospatial data and methods

 The session focused on emerging frameworks that emphasize the importance of considering structural and social determinants of health, defined as the conditions in which people are born, grow, work, live, and age (social determinants) and the wider set of forces and systems shaping the conditions of daily life (structural determinants) by the World Health Organization. The session considered these concepts and constructs and relevant conceptual frameworks for understanding their impact on health. Shariff-Marco’s presentations focused on how to study neighborhood attributes, particularly those related to the social and built environments, including conceptual frameworks as well as how to measure these for cancer epidemiologic studies.

2:30 p.m. – 4:00 p.m. | Educational Session: “Genetic Ancestry, Tumor Subtype and Somatic Genomic Landscape”

, MD, an internal medicine specialist and UCSF professor of Medicine, presented “

Genetic ancestry and somatic mutational landscape in >40,000 breast cancer patients

 Genetic ancestry is a variable frequently considered in studies of germline genetic risk. However, less is known about the importance of genetic ancestry in studies of somatic (acquired) mutations in cancer. Ziv discussed different approaches to inferring genetic ancestry using genotype data. In addition, he illustrated how genetic ancestry is related to somatic mutations and copy number aberrations in a dataset of >40,000 breast tumors.

1:00 p.m. – 2:30 p.m. | Major Symposium: Socioeconomic Contributions to Cancer Health Disparities

, MPH, PhD, an epidemiologist and UCSF professor of Epidemiology and Biostatistics, served as chairperson for the symposium and also presented “

Multi-level socioeconomic contributions to cancer health disparities from concept to measurement to practice

 This session reviewed current frameworks for conceptualizing and measuring the impacts of social and socioeconomic factors at multiple levels, and 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.

Mini-Symposium: CL01.03 - Biomarkers Predictive of Therapeutic Benefit

, 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

 Wolf reported on the performance of ImPrint in HR+HER2- patients from five immuno-oncology (IO) arms from I-SPY2.2 breast cancer trial. I-SPY2 was the first randomized trial to examine the efficacy of IO therapy in high-risk HR+HER2- breast cancer where most IO arms showed improved efficacy relative to control. The study also previously showed immune-gene expression signatures associate with pathologic complete response (pCR) in HR+HER2- treated with IO, and the research team developed a clinically applicable Immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the Response Predictive Subtypes for the trial.

Presidential Select Symposium: Cancer Immunotherapy – Where Do We Go from Here?

, 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 from 

 Marson discussed the power of using 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.

Clinical Trials Plenary Session: Advances in Targeted Therapy

, MD, a medical oncologist, Winterhof Family Endowed Professorship in Breast Cancer, and director of Breast Oncology Trials and Clinical Education at UCSF, was a discussant for 2 UK trials called the 

., 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 neoadjuvant setting.

10:15 a.m. – 11:45 a.m. | Major Symposium: Advances in Pediatric Cancer: Mechanisms, Vulnerabilities, and Translation 

, MD, UCSF chief of Pediatric Oncology, presented 

“Identification of novel osteosarcoma subtypes based on epigenetic and genomic analysis

 This session spotlighted recent advances pertinent to clinically aggressive childhood cancers, including novel epigenetic subtypes of osteosarcoma, and determinants of malignant transformation, disease progression, and treatment response in the pediatric setting. The session also included a discussion of strategies for rapid translation of novel molecular and mechanistic insights into improved diagnostics and treatments for affected children.


Sweet-Cordero also served as chairperson for

Town Hall Meeting: Then and Now: Updates in Pediatric Cancer Predisposition— A Pediatric Cancer Working Group Town Hall Meeting

Sunday, April 7, from 6:00 p.m. – 8:30 p.m

. He is chair of AACR’s Pediatric Cancer Working Group (PCWG).

Mini-symposium: Novel Molecular Targets and Biomarkers

, MS, cancer immunotherapy Ph.D. 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

 Kwok discussed his glioma study, which included development of a novel comprehensive in silico pipeline for detecting tumor-specific splicing events (neojunctions), and across multiple cancer types. He discussed how the research successfully identified a new class of tumor-wide, public, alternatively spliced neoantigens that elicit CD8+ T-cell-mediated immune responses that may offer an off-the-shelf immunotherapy approach that tackles the critical challenge of intratumor heterogeneity in immunotherapy resistance.

, MD, an otolaryngologist and associate vice chancellor for clinical and translational research at UCSF, led a “meet the expert session” on the topic of “

Identifying and Measuring Gender Inequities in Science and Medicine

.” She presented the findings of a qualitative research study she conducted using in-depth, in-person interviews with 52 women and 52 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 this session, she explored the institutional metrics that should be evaluated to identify, track, and assess potential interventions designed to mitigate inequities.

10:15 a.m. – 11:45 a.m. | Major Symposium: Health Behavior Practices after Cancer Diagnosis to Deter Cancer Progression and Death: Evidence, Gaps, and Solutions

, ScD, the Steven and Christine Burd-Safeway Distinguished Professor of Epidemiology and Biostatistics at UCSF, served as chairperson for this symposium 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 all-cause death. 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.

Advances in Diagnostics and Therapeutics session: KRAS: Broadening the Attack Beyond G12C with Small Molecules and Immuno-Oncology

, PhD, UCSF professor of Cellular and Molecular Pharmacology and AACR Academy Fellow, chaired this session and presented “

Expanding K-Ras covalent chemistry for targeting K-Ras (G12D)

. 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 discussed the latest findings in KRAS chemistry and structure in the continuing search for novel small molecules that target G12D mutations.

12:30 p.m. – 2:00 p.m. | Major Symposium: Discovering and Broadening the Therapeutic Modalities of Immune Therapy

, 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

 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.

12:30 p.m. – 2:00 p.m. | Advances in Prevention Research session: “From Precursors to Prevention: How Research into Cancer Precursor Lesions Creates Prevention Opportunities” 

, 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

 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. These differences likely indicate variations in the respective cell of origin, their differentiation and functional stage, determining specific vulnerabilities along which tumor evolution can occur.

Town Hall Meeting: Advancing Radiation Oncology with Artificial Intelligence: A Radiation Science and Medicine Working Group Town Hall Meeting

, PhD, assistant professor in the UCSF department of Radiation Oncology, was an invited speaker presenting “

Causal Targeted Machine Learning for Real-World Evidence Generation in Oncology: Assessing Causal Effects of Radiation Toxicity on Overall Survival in Stage III Non-Small Cell Lung Cancer

.” His study explores the causal impact of radiation-induced toxicities on overall survival in stage III non-small cell lung cancer patients undergoing proton radiation therapy. The study findings suggest the need for personalized treatment strategies that balance treatment intensity with toxicity management. He also explained how the study methodology provides a step-by-step causal roadmap for generating reliable real-world evidence, setting a precedent for applying such techniques in radiation oncology to support clinical and regulatory decision-making, and ultimately enhance patient care.

Major Symposium: Cancer Metabolism Across Scales: From Organelles to Organisms

, PhD, UCSF associate professor of Anatomy, presented “

Lysosome dependent metabolic adaptation in pancreatic cancer

The interdisciplinary session will convene researchers working at the forefront of cancer biology and metabolism and explore how metabolic processes, from organelles to entire organisms, influence cancer development and progression. Perera was among the experts to discuss metabolic reprogramming in cancer cells and the roles that cellular components like mitochondria, lysosomes, and autophagy play in finding new therapies to treat the disease.

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Targeted therapy, genomics, and treatment disparities were among the topics that were presented by researchers from UCSF at the 2024 AACR conference.

Advances in Targeted Therapy, Treatment Disparities Among Cancer Conference Talks

Immunotherapies using engineered T cells have ushered in a new era in cancer treatment, but they have their limits. They may cause adverse effects or stop working, and they do not work at all against 90% of cancers.

Now, scientists at UC San Francisco and Northwestern Medicine may have found a way around these limitations by borrowing a few tricks from cancer itself.

By studying mutations in malignant T cells that cause lymphoma, they zeroed in on one that imparted exceptional potency to engineered T cells. The team inserted a gene for this unique mutation into normal human T cells, which made them more than 100 times more potent at killing cancer cells. They kept the tumors at bay for many months, showing no signs of becoming toxic.

While current immunotherapies work only against cancers of the blood and bone marrow, the new approach was able to kill solid tumors derived from skin, lung and stomach tissues in mice. The team has already begun working toward testing this new approach in people.

The breakthrough was inspired by the martial arts principle of using an opponent’s strength against them, said 

, PhD, a co-author on the study and associate professor of microbiology and immunology.

“We’ve used the mutations that give cancer cells their staying power to engineer what we call a ‘Judo T-cell therapy’ that can survive and thrive in the harsh conditions that tumors create,” he said.

Immunotherapy has proved difficult against most cancers because a solid tumor creates an environment focused on sustaining itself, redirecting resources like oxygen and nutrients for its own benefit. Often, cancerous tumors hijack the body’s immune system, causing it to defend, rather than attack, the cancer.

Not only does this impair the ability of regular T cells to target cancer cells, it also undermines the effectiveness of engineered T cells that are used in immunotherapies, which quickly tire against the tumor’s defenses. For immunotherapy treatments to work under those conditions, “We need to give healthy T cells abilities that are beyond what they can naturally achieve,” said Roybal, who is also a member of the 

Gladstone Institute of Genomic Immunology

Using such T cells from patients with lymphoma, the UCSF and Northwestern teams screened 71 mutations, eventually isolating one that proved both potent and non-toxic, subjecting it to a rigorous set of safety tests.

“This approach performs better than anything we’ve seen before,” said Jaehyuk Choi, MD, PhD, an associate professor of medical dermatology, as well as biochemistry and molecular genetics, at Northwestern University Feinberg School of Medicine.

“Our discoveries empower T cells to kill multiple cancer types and have the potential to offer cures to people who have a poor prognosis,” he said, noting that because cell therapies live and grow inside the patient, they can provide long-term immunity against cancer.

In collaboration with the Parker Institute for Cancer Immunotherapy and venture capital firm Venrock, Roybal and Choi have launched a new company, Moonlight Bio, to realize the potential of their “judo” approach. Their first project is developing a lung cancer therapy that they hope to begin testing in people within the next few years.

“We see this as the starting point,” Roybal said. “There’s so much to learn from nature about how we can enhance these cells and tailor them to different types of diseases.”

The research was supported by the Parker Institute for Cancer Immunotherapy, NIH grants (grants F30 CA265107, T32 CA009560, 1DP2AI136599-01 and DP2 CA239143), Cancer Moonshot grant U54 CA244438, the Mark Foundation for Cancer Research, the Bakewell Foundation, and UCSF Helen Diller Family Comprehensive Cancer Center.

Roybal and Choi are inventors on patents related to these discoveries and are co-founders and equity holders in Moonlight Bio.

A genetic mutation that makes cancer cells hardy can be engineered into T cells, giving them superhuman strength.


In Judo Move, Scientists Use Cancer’s Strength to Fight Against It

Many physicians are unfamiliar with how the Food and Drug Administration (FDA) regulates new drugs and medical devices, and they may be under the impression that the data supporting these approvals are more rigorous than they are, according to a national survey of physicians conducted by researchers at UC San Francisco (UCSF).

Physicians said they wanted to see more rigorous pre-market evidence, as well as regulatory action against drugs and devices that do not demonstrate safety and effectiveness after they have been approved for use.

“Many of the physicians we queried felt that the FDA has become more lenient over time,” said first author 

, MD, MHS, a UCSF cardiologist, assistant professor of medicine, and member of the Philip R. Lee Institute for Health Policy Studies. “Physicians need – and want – to know if a drug or device was rigorously studied before they can make recommendations to their patients.”

Physicians’ knowledge of the FDA’s approval process is important in informing clinical decisions and patient discussions. In recent years, several aspects of the FDA review process have changed, including the nature of the evidence required for approval. One of the most prominent modifications is the increasing use of expedited pathways to make potentially promising drugs and devices available to patients based on earlier-stage data.

Among the 509 physicians participating in the survey, 41% reported a moderate or better understanding of the FDA’s drug approval process, and 17% reported a moderate or better understanding of the FDA’s medical device approval process. Fifty-nine percent of physicians thought that the FDA’s current bar for approval of new drugs was about right, with 66% feeling similarly for new devices. Yet, more than a quarter of the respondents thought that the FDA was too flexible in the data accepted for new approvals for both drugs and devices.

Nearly all physicians thought that randomized, blinded trials that met primary endpoints should be required to secure regulatory approval, with majorities saying that the FDA should require two or more randomized controlled trials of most new drugs (57%) and for most new devices (60%). Nearly all physicians thought the FDA should revoke approval for drugs in the accelerated approval program (95%) or breakthrough devices (89%) that did not show benefit in post-approval studies.

“Physicians overwhelmingly felt that randomization, blinding, and meeting primary endpoint thresholds were important characteristics of trials used to support regulatory approval,” Dhruva said. “Despite these preferences, the proportion of studies leading to FDA approval that feature these characteristics has fallen in recent years.”

The authors note that the prevalence of physicians reporting a lack of understanding of drug and medical device approval reflects the limited coverage of these topics during medical education. They also suggest that the FDA could explain clearly and concisely how and why a drug was authorized, including its risk-benefit assessment, and what knowledge gaps remain.

 Rita F. Redberg, MD and Robin Z. Ji, of UCSF; Aaron S. Kesselheim, MD, Zhigang Lu, and Jonathan J. Darrow, SJD, of Harvard University, and Steven Woloshin, MD, of Dartmouth University.

 This study was funded by the Greenwall Foundation and Arnold Ventures.

A national survey conducted by UCSF researchers reveals that many physicians are unfamiliar with how the FDA regulates new drugs and medical devices.

UCSF Helen Diller Family Comprehensive Cancer Center

Articles

Advances in Targeted Therapy, Treatment Disparities Among Cancer Conference Talks

In Judo Move, Scientists Use Cancer’s Strength to Fight Against It

Survey Shows Physicians Don’t Understand FDA’s Approval Process