Molecular Oncology Program

Program Leaders



Training and Education Liaison: Eric Collisson, MD

Community Engagement Liaison: Hani Goodarzi, PhD

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.

Targeting signal transduction in cancer  

Kevan Shokat, PhD and James Wells, PhD collaborated to identify small molecules that irreversibly bind to a common oncogenic mutant, K-Ras. These compounds were discovered using the ‘disulfide tethering’ technology developed by Wells, and currently supported by the SMD directed by Michelle Arkin, PhD, that employs strategically placed cysteine residues to ‘tether’ cysteine containing small molecules from a designed small molecule library. The mutant cysteine in K-Ras. provided the tether for small molecule binding that does not affect the wild-type protein. These results led to the formation of Wellspring Biosciences, a company focused on the discovery and development of small molecule drugs that target signal transduction networks for the treatment of cancer such as the K-Ras inhibitors. They also resulted in NCI funding. to further probe the ability to drug the switch-II pocket of K-Ras.

 

In the previous grant cycle, Pamela Munster, MD in collaboration with multiple members of the BR Program (Mark Moasser, MDHope Rugo, MDJo Chien, MD; and Michelle Melisko, MD) demonstrated in preclinical models that HDAC2 inhibition reverts aberrant estrogen receptor signaling and independent action, thereby mitigating hormone therapy resistance. During the current grant cycle, this work was subsequently translated by Munster into two clinical trials: one as an institutional trial, and the second completed in collaboration with Syndax. Based on this work, the HDAC inhibitor entinostat received breakthrough status to reverse hormone therapy resistance in 2013. The benefits of entinostat in reversing hormonal therapy resistance is now being studied in a multicenter NCTN (Alliance) phase III registration trial). Munster is continuing laboratory investigations to define host factors that predict acetylation changes in tumors and in immune cells.

Targeting epigenetic modulation, cellular homeostasis, and the tumor environment

Jonathan Weissman, PhD played a central role in the development of CRISPRi/a technology systematically evaluating the rules by which dCas9 can effectively control the volume of expression of any transcript, when fused to transcriptional activation or repressor domains. He subsequently developed Perturb-seq, which pairs CRISPRi/a with advances in droplet-based single cell RNA-seq to enable the systematic exploration of gene function with ultra-rich phenotypic readouts.

Each of these technologies has been used to map out cancer vulnerabilities and led to the formation of KSQ Therapeutics, a platform technology company focused on screening the human genome to identify novel therapeutic targets associated with cancer. For example, a role of P97 in cancer therapy was identified that led to the inception of a first-in-human phase I trial studying p97 inhibitors in solid tumors (Munster) and hematologic malignancies (Jeffrey Wolf, MD). Subsequently, an NCI CTD renewal grant application that included Trever Bivona, MD, PhDWeissmanSourav Bandyopadhyay, PhDFrank McCormick, PhD, FRS; and Alan Ashworth, PhD, FRS received a perfect priority score to build a technological and intellectual foundation that will allow for the systematic exploration of the functional roles of genetic lesions identified in large-scale cancer genome projects.

Determining the impact of germline genetics on cancer susceptibility, progression, treatment choices, and response.

Margaret Wrensch, PhDPaige Bracci, PhD, MPH, MSJoe Wiemels, PhD ; and John Wiencke, PhD, and Kyle Walsh, PhD (former CG Program member) have continued to make central discoveries that are helping to decipher the genetic basis of adult gliomas . Most recently, they have led large-scale projects that identified genetic variants that define several brain tumor subtypes with differing survival profiles. They further showed that variants in TERC and TERT help drive telomere length. This important work demonstrated that germline SNPs in genes that affect the length of telomeres are important susceptibility factors for glioma. Their data motivate future work on the potential biological and translational mechanisms underlying development of cancer due to genetic instability arising from disruption of telomere length, and form a natural bridge to the work by the group of Boris Bastian, MD, PhD described below. Bastian, Executive Director of the new UCSF Clinical Cancer Genomics Laboratory (CCGL), has continued to make groundbreaking discoveries that illuminate the genetic changes in different subtypes of melanoma. In the first study of its kind, he carried out a dissection of the progressive events in melanomas from the earliest lesions through to metastasis, identifying TERT promoter mutations at a surprisingly early stage in neoplastic progression. TERT promoter mutations are also highly prevalent in gliomas, as shown by NE Program member Joseph Costello, PhD, and have led to development of a start-up company (Telo Therapeutics) with the goal of developing novel drugs that target the effects of these mutations. These studies have redefined the genetics of melanoma development and progression, identifying recurrent mutations or novel gene fusions in several targets (GNAQ, GNA11, c-KIT, BRAF, NTRK3) that provide new opportunities for translational applications in prevention and treatment.

Exploiting somatic tumor genomic events for precision medicine drug development and targeted therapy

Allan Balmain, PhD, FRSDavid Quigley, PhD, and international collaborators compared the genetic architecture of mouse tumors induced by exogenous mutagens, and those arising in genetically engineered cancer models. They demonstrated that chemically induced tumors mimic much more closely the patterns of changes found in equivalent human cancers. The data have revived interest in environmentally induced tumors as models for cancer therapy, in particular for immunotherapy, which is dependent largely on a high mutation burden. They further demonstrated that tumors induced by chemical mutagens carry the genome-wide mutation signatures of exposure. These results led to the award of a major $30M grant from Cancer Research UK to a consortium of several institutions, including UCSF, in which Balmain is playing a key leadership role to carry out a sequencing initiative to identify mutation signatures in mouse and human cancers.

Developing new biological insights and combinatorial therapies through systems views of cancer

Trever Bivona, MD, PhD is analyzing the genetics and responses of human cancers to targeted therapies. Bivona collaborated extensively with Eric Collisson, MD and Martin McMahon, PhD (former ET Program member) to show that the Hippo effector YAP, Anaplastic Lymphoma Kinase (ALK), or AXL kinase promote resistance to EGFR/Ras/Raf-targeted cancer therapies. These data offer new possibilities to prevent or reverse drug resistance using combined or sequential treatment with clinically approved inhibitors of EGFR/Ras signaling and novel agents targeting the Hippo/YAP pathway.

Roster of Molecular Oncology Program

Total: 95 members.

For details on membership criteria, please see our membership page.