Mark Moasser, MD

Professor In Residence
Department of Medicine
mmoasser@medicine.ucsf.edu

The idea that cancers can be treated by targeting their driving oncogenes is now a firmly established form of treatment extensively deployed in the practice of oncology. However the experience with the first generation of such oncogene-directed therapies has shown a range of results and it is now evident that this treatment paradigm is more complex than previously envisioned. We now need to understand the successes and failures of this first generation of therapeutics in order to lay the groundwork for the next generation of far more effective and hopefully eradicative therapies. Our group has been focusing on two of the tyrosine kinase families strongly implicated in human cancers; the Human Epidermal Growth Factor Receptor (HER) family of receptor tyrosine kinases and the Src family of non-receptor tyrosine kinases.  

Towards far more effective therapies for HER2-driven cancers

Amplification of HER2 underlies the biology of 25% of breast cancers as well as subsets of many other types of epithelial cancers. Many of the drugs designed to target HER2 show modest or incremental anti-tumor activity in patients. Understanding and overcoming this limitation is a principal goal of our research program. Our laboratory discovered the previously underestimated role of HER3, and showed that the resiliency lies in the HER2-HER3 complex which is constitutively activated by HER2 overexpression and is far more difficult to inactivate than previously thought. We are currently studying how this complex is activated in the pathologic state of overexpression, how this differs from the normal physiologic mode of signaling, what are the structural determinants that are rate-limiting in the pathologic state of signaling, and define the mechanistic basis for next generations of highly effective agents that can inactivate it. This involves extensive structure-function work in biochemical assays, cancer cell lines, and mouse tumor models. We are also interested in understanding the signaling circuitry downstream of HER2-HER3 that underlies its extreme resiliency and that is reprogrammed in cancers driven by overactive HER2-HER3 signaling. In a related field, we are very interested in understanding how and why tumors acquire an apparent addiction to the HER2 oncogene such that they cannot even survive without continued hyperactivity of this oncogene. Our work is in close collaboration with a number of other UCSF labs in the fields of structural biology, biochemistry & biophysics, chemistry and drug discovery.

Deeper insights into the role of Src kinases in human cancers

Src kinases underly the tumorigenic properties of a number of animal retroviruses and like many other oncogenes, it has long been thought that their cellular homologs function as proto-oncogenes that can get activated and promote human cancers. But now 40 years after the discovery of the tumorigenic retroviral v-Src, this paradigm has failed to be confirmed for the proto-oncogene c-Src, and the role of Src kinases in human tumorigenesis remains presumptive and mechanistically undefined. Src kinases do not appear to be mutationally altered or activated in human cancers and several potent inhibitors of Src kinases have shown no anti-tumor activity in clinical trials of cancer patients. Our group is interested in the elusive question of whether and how Src kinases contribute to the development or progression of human cancers. Our studies to date have revealed that the signaling functions of Src kinases are more complex than currently understood, and their deregulation in human cancers follows a more complex paradigm than can be described by simple over-activity or that can be neutralized by targeting its catalytic activity. Extensive work is ongoing in our laboratory, with promising results already, to gain insights into how the functions of Src kinases are deregulated in human cancers.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Human Genetics
Research Summary: 
Tyrosine kinase oncogenes in human cancer

Websites

Publications: 

Differential toxicity in patients with and without DNA repair mutations: Phase I Study of Carboplatin and Talazoparib in advanced solid tumors.

Clinical cancer research : an official journal of the American Association for Cancer Research

Dhawan MS, Bartelink IH, Aggarwal R, Leng J, Zhang JZ, Pawlowska N, Terranova-Barberio M, Grabowsky JA, Gewitz A, Chien AJ, Moasser MM, Kelley RK, Maktabi T, Thomas S, Munster PN

CD318 is a ligand for CD6.

Proceedings of the National Academy of Sciences of the United States of America

Enyindah-Asonye G, Li Y, Ruth JH, Spassov DS, Hebron KE, Zijlstra A, Moasser MM, Wang B, Singer NG, Cui H, Ohara RA, Rasmussen SM, Fox DA, Lin F

A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies.

Breast cancer research and treatment

Chien AJ, Cockerill A, Fancourt C, Schmidt E, Moasser MM, Rugo HS, Melisko ME, Ko AH, Kelley RK, Korn WM, Esserman LJ, Van't Veer L, Yau C, Wolf DM, Munster PN

Effective treatment of HER2-amplified breast cancer by targeting HER3 and ß1 integrin.

Breast cancer research and treatment

Campbell MR, Zhang H, Ziaee S, Ruiz-Saenz A, Gulizia N, Oeffinger J, Amin DN, Ahuja D, Moasser MM, Park CC