The Molecular Oncology Program brings together basic cancer biologists and physician scientists to discover and test novel compounds and treatment strategies for cancer.
The overarching goal of the Molecular Oncology Program is to discover and validate therapeutic targets and subsequently identify, develop, and test novel therapeutic strategies and biomarkers.
- Theme 1: Targeting Signal Transduction in Cancer
- Theme 2: Targeting Epigenetic Modulation, Cellular Homeostasis, and the Tumor Environment
- Theme 3: Determine and Integrate the Impact of Genetics on Cancer Susceptibility, Progression, and Therapeutic Response
Theme 1: Targeting Signal Transduction in Cancer
In an interprogrammatic collaboration Okimoto, Weissman, Blakely, and Bivona used Crispr-based lineage tracing and single cell sequencing to map the metastatic trajectories of cancer cells through phylogenetic and evolutionary reconstruction in vivo to reveal the rates, routes and drivers of metastasis in cancer xenografts. Barcellos-Hoff showed that loss of TGFβ signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types. This work was supported in part by a UCSF intramural pilot award to Barcellos-Hoff and Ashworth.
Using genetic ablation and pharmacological inhibition, Bastian, Roose, and Chen showed that the PKC/RasGRP3/MAPK signaling branch is the essential component that drives the proliferation of uveal melanoma. Only inhibition of the MAPK branch but not the FAK branch synergizes with inhibition of the proximal cascade, providing a blueprint for combination therapy. Humtsoe, Ha, and Kang identified several FGFR1 variants that function through the AXL/AKT signaling pathway independent of FGF/FGFR1, desensitizing cells to FGFR1 inhibitor, suggestive of a potential resistance mechanism in adenoid cystic carcinoma.
McCormick, Moasser (BR), Bandyopadhyay, and Rubenstein (CII) took a pathway directed approach and identified signaling pathways important for cell growth. Using a patient derive xenograft drug screen platform they showed that inhibitors of PI3K and histone deacetylase (HDAC) are highly synergistic in growth inhibition and apoptosis induction in Cutaneous T-Cell Lymphoma. Kang contributed to a pivotal trial of selpercatinib that targets RET in medullary thyroid cancer which led to its FDA approval. The study was published in New England Journal of Medicine.
Kelley advanced the field of liver cancer by a landmark study on Atezolizumab and bevacizumab. Munster was part of the first study on a specific small molecule targeting KRAS G12C for the first time based on a UCSF technology.
Geng reported on the E2A-PBX1 function as a coactivator for RUNX1 and the role of Integrin α6 in drug resistance in acute lymphoblastic leukemia. Blakely studied the benefits of entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumors in early phase clinical studies.
Theme 2: Targeting Epigenetic Modulation, Cellular Homeostasis, and the Tumor Environment
In an inter and intraprogrammatic collaboration, Bivona, Bandyopadhyay, Blakely, Gubens and Jablons reported on a study to better understand the cellular and molecular mechanisms underlying lung cancer disease persistence after treatment with molecularly targeted therapies. Using single-cell RNA sequencing, they identified therapy induced evolution of human lung tumor and immune cells during targeted therapy. Gestwicki used a prodrug approach on a non-nucleoside inhibitor of the prolyl isomerase, Pin1 to develop pharmacological agents to probe the role of Pin1 in prostate and breast cancer.
Goodarzi and Warren in an intraprogrammatic collaboration on metastatic progression in colon cancer, identified a previously unknown pathway of gene expression control. Kampmann and Taunton (MO), Roybal, Shah, Wong, Wolf, and Martin (CII) used an unbiased CRISPR screen to uncover therapeutic targets that enhance multiple myeloma immunotherapy directed to BCMA, and validated them pharmacologically in a cell-based model.
Craik, Shokat, Munster, and Kirkwood received UCSF Transformative Integrated Research (TIR) funding for a proposal targeting an intracellular oncoprotein (KRas G12C) in MHC I for immunotherapy with hapten-directed antibodies. Venook reported on the effects of coffee intake on colon cancer, showing that coffee is actually prompting better survival of patients with colon cancer. Ko demonstrated that pembrolizumab was a tolerable and not inferior choice for patients with first-line, advanced gastric cancer, but pembro and chemotherapy were not superior to chemotherapy alone.
Theme 3: Determine and Integrate the Impact of Genetics on Cancer Susceptibility, Progression, and Therapeutic Response
In a continued intraprogrammatic collaboration Shain, Bastian, and Yeh developed a new approach to genotyping individual cells at a high degree of accuracy and applied the methodology on cells from normal skin. This work revealed new insights into the etiology of melanoma including the finding that melanocytes from “normal” skin are riddled with mutations known to drive melanoma.
In a highly collaborative, translational study, Atreya, Collisson, Friedlander, and Behr (ZY) used multidimensional histopathologic and genomic profiling to show that a CDH1 mutation and MET amplification in a young donor organ transmitted cancer to four transplant recipients, suggesting routine short tandem repeat testing upon diagnosis of cancer in any organ transplant recipient.
Kroetz, Rugo, and Witte showed that S1PR1 is associated with sensory peripheral neuropathy among women receiving microtubule targeting agents. Olin demonstrated the feasibility of prospective genomic profiling in acute myeloid leukemia in the BEAT AML master trial. A interprogramatic collaboration of Shieh (CC) and Ziv focused on polygenic risk scores describing the very different risk criteria of breast cancer in US Latinas and Latin American Women.
In an intra-programatic collaboration, Witte, Ziv, and Graff (PR) show that germline genetic information improves cancer risk prediction beyond known modifiable risk factors and that there exists substantial pan-cancer pleiotropy. Ziv identified a significant germline genetic contribution to several important aspects of the tumor immune environment including signatures of interferon signaling in the tumor and signatures of T-cell and NK cells in the tumors tying autoimmunity to cancer immune response.
Roster of Molecular Oncology Program
For details on membership criteria, please see our membership page.