Scientific Accomplishments

M.McMahon P.Munster
Program Leader: Pamela Munster, MD
Program Co-Leader: Martin McMahon, PhD

> Targeting Signal Transduction Pathways
> Targeting DNA Replication and Genome Integrity
> Angiogenesis and Apoptosis
> Genetic Determinants of Sensitivity and Resistance


Theme 1: Targeting Signal Transduction Pathways

Dr. Martin McMahon and colleagues have demonstrated the importance of the WNT®-catenin®c-MYC pathway in the early stage proliferation of BRAFV600E-induced lung and other tumors (Gustafson et al., Cancer Cell, 2014; Juan et al., Genes Dev, 2014).

A collaboration between Drs. Kevan Shokat, Frank McCormick, and Alma Burlingame employed a combined chemogenomics and chemoproteomics approach to identify drug-induced RAS®RAF®MEK complex formation in a subset of BRAF-mutant cancer cells characterized by primary resistance to vemurafenib. Overall, the collaboration revealed that the signaling plasticity exerted by primary resistant BRAF-mutant cells is achieved by their ability to mimic signaling features of oncogenic RAS, a strategy they termed "oncogene mimicry." This model may guide future strategies for overcoming primary resistance observed in these tumors (Sos et al., Cell Rep, 2014).

Drs. William Weiss, Kevan Shokat, and Kate Matthay demonstrated that proteolytic degradation of MYCN protein, a key driver of neuroblastoma, is regulated in part by a kinase-independent function of Aurora A kinase. Moreover, they described a class of inhibitors that disrupts the native conformation of Aurora A and promotes NMYC degradation in multiple NMYC-driven cancers (Gustafson et al., Cancer Cell, 2014). Drs. Sabrina Ronen and Davide Ruggero (Prostate Cancer Program) collaborated to demonstrate that the MYC oncoprotein coordinates the production of the two most abundant classes of cellular macromolecules—proteins and nucleic acids—in cancer cells through regulation of the expression of phosphoribosyl-pyrophosphate synthetase 2 (PRPS2) (Cunningham et al., Cell, 2014). Drs. Shokat and Weiss further studied the effects of Aurora kinase inhibition in radiation therapy in glioblastoma with colleagues from the Neurologic Oncology Program (Li et al., Mol Cancer Ther, 2015).

The UCSF imaging group, Drs. Dan Vigneron, Miguel Pampaloni, Sabrina Ronen, and Henry Van Brocklin are pioneers in PET tracer imaging. With the support of the CCSG and a P41 center grant, Dr. Vigneron, Nelson (Neurologic Oncology Program), Ronen, and Munster are conducting several peer-reviewed projects evaluating the PI3 kinase pathway inhibition in prostate cancer, glioma, and breast cancer. They are also using hyperpolarized [1-13C]dehydroascorbate MR spectroscopy in a murine model of prostate cancer (Chaumeil et al., Cancer Res, 2014; Park et al., Cancer Res, 2014)

Under Dr. Munster’s leadership, the early-phase clinical trials group continues to translate findings to clinical trials. Therapeutic interventions involving the inhibition of the PI3 kinase, RAS, RAF pathway are being studied in several phase I trials with transition into phase II trials in breast cancer and head and neck cancer and melanoma.

Theme 2: Targeting DNA Replication and Genome Integrity

In a collaboration involving Drs. Frank McCormick, Kevan Shokat, and Andrei Goga, engineered isogenic cells were used to generate a systematic and quantitative chemical-genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. This dataset strongly predicted drug responses found in cancer cell line collections, indicating that isogenic cells can model complex cellular contexts. This scalable approach enables the prediction of drug responses from patient data and can accelerate the development of new genotype-directed therapies (Martins et al., Cancer Discov, 2015).

During the past year, Dr. Elizabeth Blackburn’s lab has made novel findings about hTERT, the gene encoding the core component of telomerase, the RNP complex enzyme that elongates and protects telomeres. Moreover, she has shown that telomere attrition in in healthy older women may be linked to stress and lifestyle (Puterman et al., Mol Psychiatry, 2014).

Dr. Goga’s work on specific inhibition of CDK2 kinase activity showed that CDK2 inhibition drastically diminishes anchorage-independent growth of human cancer cells and cells transformed with various oncogenes. He has shown that CDK2 activity is necessary for normal mammalian cell cycle progression and may be a good therapeutic target. This has led to a clinical trial studying a select CDK inhibitor in MYC-amplified tumors in the phase I group (Dr. Amy Chien, PI, Breast Oncology Program).

Dr. David Morgan’s lab studies fundamental problems in cell division, using yeast as a model system, with a primary focus on the control of chromosome segregation in anaphase of mitosis. In the past year they discovered that Sgo1 recruits PP2A to chromosomes to ensure sister chromatid bi-orientation during mitosis. His group further showed that CDK1 phosphorylates Iqg1 and plays an important role in actomyosin ring assembly prior to cytokinesis (Eshleman et al., J Cell Sci, 2014; Naylor et al., J Cell Sci, 2014).

Theme 3: Angiogenesis and Apoptosis

The laboratory of Dr. James Wells explores the molecular basis for programmed cell death (Rettenmaier et al., Proc Natl Acad Sci USA, 2014; Wells et al., Science, 2014). In dissecting programmed pathways, he has defined several crucial components leading to cell death, including the roles of chemical fibrils and small-molecule peptide docking motifs (Julien et al., Nat Chem Biol, 2014).

Dr. Mark Moasser’s work on the role of HER3 in cell death, tumor perfusion, and drug resistance has been explored in three clinical trials testing a monoclonal antibody against HER3, high doses of lapatinib, and a highly potent HER2 / HER3 inhibitor. This trial is a collaboration between the Developmental Therapeutics and Breast Oncology Programs and has been presented over the past year (Chien et al., J Clin Oncol, 2014). Dr. Ajay Jain continues to make significant advances in computational drug discovery using high-throughput computational screening for the discovery of promising small molecules for modulation of specific biological targets. His work allows for better prediction of off-target effects of drugs using data fusion evaluation (Yera et al., Pac Symp Biocomput, 2014).

Theme 4: Genetic Determinants of Sensitivity and Resistance

Drs. Neil Shah and Kevan Shokat collaborated and reported a novel chemical strategy for treating Acute Myeloid Leukemia (AML): they selectively inhibited FLT3 while avoiding KIT inhibition using the staurosporine analog, Star-27. Star-27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared to KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors (Warkentin et al., Elife, 2014). In further studies, Drs. Charlie Craik and Shah developed plasmon ruler nanosensors to monitor apoptosis in leukemias (Tajon et al., ACS Nano, 2014).

Dr. Frank Szoka’s lab continues to use novel approaches to devise vaccine, drug, and nucleic acid delivery systems to treat cancer. In a recent study, the group showed that fusion of a short immunoglobulin-binding peptides to recombinant proteins can substantially prolong their half lives (Sockolosky et al., PLoS One, 2014). In collaboration with the thoracic oncology group, Dr. David Jablons has identified recurrent FGFR3-TACC3 fusion oncogenes in lung adenocarcinoma (Capelletti et al., Clin Cancer Res, 2014).

A collaboration between the Developmental Therapeutics and Hematological Malignancies Programs (Martin, Rubenstein, and Munster) has shown that CD38 inhibition in myeloma is a valuable target (presented at ASH 2014). Dr. Rubenstein has shown that intrathecal administration of rituximab is effective in CNS lymphomas via Complement activation (Kadoch et al., Clin Cancer Res, 2014).

Major findings from Dr. Deanna Kroetz’s laboratory in breast cancer pharmacogenomic studies include the identification of additional candidate genes and pathways as predictors of taxane-induced peripheral neuropathy. The collaboration with CALGB revealed that inheritance of paclitaxel-induced sensory peripheral neuropathy is driven by axon outgrowth gene sets (Chhibber et al., Pharmacogenomics J, 2014).