Exploiting Molecular Oncology To Trigger Tumor Cell Death
Cancer occurs when a single cell acquires multiple genetic mutations that result in uncontrolled growth and survival. The tumor cell becomes addicted to these mutations and their activated signaling pathways. Our goal is to understand, exploit and target these tumor-specific vulnerabilities. To this end we have two working groups in the lab, Tumors’n’Targets and Death’n’Drugs. Our ideas are simple and relevant, and our approach is 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. We are
identifying the target genes regulated by Myc, the cofactors
recruited by Myc and the post-translational modifications
regulating these processes. Targeting Myc’s potent transforming
activity through the development of novel inhibitors is a major
area of investigation. Interestingly, for a non-transformed cell with deregulated Myc expression to develop into a fully malignant cancer, it is essential that Myc’s ability to potentiate apoptosis be overcome. We aim to understand the molecular mechanism of Myc-induced apoptosis and identify genetic events that can block this programmed cell death, to cooperate with Myc in tumour progression. To achieve these goals we use state of the art technologies, including ChIP-chip, high-throughput FRET/FLIM as well as functional cloning, and have established several tissue culture and animal models for our work, including leukemia, breast, neuroblastoma, and lung cancers.
The other major area of focus 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 tumor-specific apoptosis. Statins block HMGCoA reductase, the rate-limiting enzyme of the mevalonate pathway. This is a basic biochemical pathway essential for cellular metabolism. Because statins are an approved drug for use in humans, we can immediately fast-track statins to impact patient care. To this end, our research goals are to understand why certain tumor-types are highly sensitive to statin-induced apoptosis. Moreover, we aim to determine how best to use statins in treatment regimes in combination with traditional and molecular targeted therapeutic options. Recent evidence in the lab suggests that statins can also sensitize tumor cells to undergo apoptosis in a mevalonate-independent mechanism. Biomarkers of sensitivity and response are also a major focus. The role of statins and the sensitivity of the tumor stem cell is also a key area of investigation. Tumor types under study include leukemia, multiple myeloma and ovarian cancer, however, several others neoplasias are also potential targets.
- Carolyn Goard
- Ali Fatehi Hassanabad
- Sam Sulgi Kim
- Lindsay Lustig
- Stefanie Oliveri
- Aleksandra Pandyra
- Amanda Wasylishen
- James Clendening
- Danijela Konforte
- Romina Ponzielli
Selected References:Link to Pubmed Publications
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.
Ponzielli, R., Boutros, P., Katz, S., Stojanova, A., Hanley, A., Khosravi, F., Bros, C., Jurisica, I., Penn, L.Z. Optimization of experimental design parameters for high-throughput chromatin immunoprecipitation studies. Nucleic Acids Research 2008 December; 36(21):e144
Boutros PC, Lau SK, Pintilie M, Liu N, Shepherd FA, Der SD, Tsao MS, Penn LZ, Jurisica I. Prognostic Gene Signatures for Non-Small Cell Lung Cancer. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2824-8.
Stojanova, A., Penn, L.Z. The Role of INI1/hSNF5 on Gene Regulation and Cancer. Biochem Cell Biol. 2009 Feb;87(1):163-77. Invited and peer-reviewed review.
Meyer N, Kim SS, Penn LZ. The Oscar-worthy role of Myc in apoptosis. Semin Cancer Biol. 2006 Aug;16(4):275-87. Review
Kim SS, Shago M, Kaustov L, Boutros PC, Clendening JW, Sheng Y, Trentin GA, Barsyte-Lovejoy D, Mao DY, Kay R, Jurisica I, Arrowsmith CH, Penn LZ. CUL7 is a novel antiapoptotic oncogene. Cancer Res. 2007 Oct 15;67(20):9616-22.
Wong WW, Dimitroulakos J, Minden MD, Penn LZ. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002 Apr;16(4):508-19. Review
Wong WW, Clendening JW, Martirosyan A, Boutros PC, Bros C, Khosravi F, Jurisica I, Stewart AK, Bergsagel PL, Penn LZ. Determinants of sensitivity to lovastatin-induced apoptosis in multiple myeloma. Mol Cancer Ther. 2007 Jun;6(6):1886-97.