Exploiting Molecular Oncology To Trigger Tumour Cell Death
Cancer occurs when a single cell acquires multiple genetic and epigenetic mutations that result in uncontrolled growth and survival. The tumour cell becomes addicted to these mutations and their activated signaling pathways. Our goal is to understand, exploit and target these tumour-specific vulnerabilities. Our ideas are relevant to cancer patient care, and our approaches are novel and achievable. We focus on two major areas.
The first area of focus is the regulation and function of the Myc oncogene. Myc is deregulated in >50% of human cancers and functions as a regulator of gene transcription. Developing inhibitors to target Myc would mark a key advance, however Myc is not ‘druggable’ by conventional approaches, thus novel strategies are required. We aim to understand how Myc is regulated at the level of stability and activity so these signaling pathways can be exploited for the development of anti-Myc therapies. In particular we are using new technologies to identify Myc post-translational modifications, Myc:protein interactions and Myc target genes that are essential for Myc’s potent transforming activity, Driving Myc destruction or inhibiting Myc activity at these points of regulation has potential to block Myc and impact tumour cell growth and viability. Such inhibitors of Myc’s oncogenic activity are under development.
The other major area of focus in the Penn lab is in the use of statins as anti-cancer agents. Statins are a family of drugs used routinely in the control of hypercholesterolemia that we and others, have shown can trigger tumour-specific apoptosis. Statins block HMGCoA reductase, the rate-limiting enzyme of the mevalonate pathway. We have shown that deregulated expression of the mevalonate pathway can contribute to tumorigenesis and cancer cells are preferentially dependent on the end-products of this basic metabolic pathway. Because statins are approved for use in humans, we can immediately fast-track statins to impact patient care. Our research goals are to understand the molecular basis of why certain tumor-types are highly sensitive to statin-induced apoptosis and how to best use statins as anti-cancer therapeutics.
- Manpreet Kalkat
- William Tu
- Diana Resetca
- Corey Lorenco
- Rosemary Yu
- Joseph Longo
- Pete Mullen
- Dharmesh Dingar
- Jason DeMelo
Selected References:Link to Pubmed Publications
Pandyra, AA., Mullen, PJ., Goard, CA., Ericson, E., Sharma, P., Kalkat, M., Yu, R., Pong, JT., Brown, KR., Hart, T., Gebbia, M., Lang, KS., Giaever, G., Nislow, C., Moffat, J., Penn, LZ. Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death. Oncotarget. In Press.
Dingar, D., Kalkat, M., Chan P.K., Srikumar, T., Bailey, S., Tu, W., Coyaud, E., Ponzielli, R., Kolyar, M., Jurisica, I., Huang, A., Lupien, M., Penn, LZ.*, Raught B*. BioID identifies novel c-MYC interacting partners in cultured cells and xenograft tumors. Journal of Proteomics. 2015 April 6, 118:95-111. * Co-authors.
Pandyra, A., Mullen, P., Kalkat, M., Yu, R., Pong, J., Li, Z., Trudel S., Lang, K.S., Minden, M., Schimmer, A., Penn, L.Z. Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop. Cancer Research 2014 Sep 1;74(17):4772-82.
Wasylishen AR, Kalkat M, Kim SS, Pandyra A, Chan PK, Oliveri S, Sedivy E, Konforte D, Bros C, Raught B, Penn LZ. MYC activity is negatively regulated by a C-terminal lysine cluster. Oncogene. 2014 Feb 20;33(8):1066-72
Goard CA, Chan-Seng-Yue M, Mullen PJ, Quiroga AD, Wasylishen AR, Clendening JW, Sendorek DH, Haider S, Lehner R, Boutros PC, Penn LZ. Identifying molecular features that distinguish fluvastatin-sensitive breast tumor cells. Breast Cancer Research and Treatment. 2014 Jan;143(2):301-12.
- Wasylishen, A.R, Chan-Seng-Yue, M, Bros, C., Dingar, D., Tu, W., Kalkat, M., Chan, P.-K., Mullen, P.J., Huang, L., Meyer, N., Raught, B., Boutros, P.C., Penn, L.Z. MYC phosphorylation at novel regulatory regions suppresses transforming activity. Cancer Research. 2013 Nov 1;73(21):6504-15.
Tu WB, Helander S, Pilstål R, Hickman KA, Lourenco C, Jurisica I, Raught B, Wallner B, Sunnerhagen M, Penn LZ. Myc and its interactors take shape. Biochim Biophys Acta. 2015 May;1849(5):469-83. Peer-reviewed Review.
Pandyra, A., Penn, L.Z. Targeting Tumor Cell Metabolism via the Mevalonate Pathway: Two Hits are Better Than One”. Molecular & Cellular Oncology. 2014 Dec; 4(1):e969133
Clendening, JW, Penn, LZ. Targeting tumor cell metabolism with statins. Oncogene, 2012 Nov 29;31(48):4967-78.
Meyer, N., Penn, L.Z. Reflecting on 25 Years with MYC. Nature Reviews Cancer. 2008 December; 8(12): 976-90. *Invited and peer-reviewed review.