Trainee Spotlight: Alexander Deneka, MD, PhD
Medicine and biology have always been a significant part of my life. Both of my parents are physicians, and they attracted my great interest to disease management since early childhood. My initial medical training (MD degree obtained from Moscow State University in 2010), not only provided me with a diverse educational background—which also broadened my view of science—it afforded me many different perspectives and skill sets for approaching difficult, fundamental questions in biology and medicine. During my subsequent residency in General Surgery at the N.V. Sklifosovsky Emergency Institute Hospital, Moscow, Russia, I took care of multiple patients with lung cancer and became very concerned about the limited treatment options available. I started to understand that deep investigation of the mechanisms of disease development might yield novel treatment approaches for patients. This growing interest in oncology, and a desire to improve patient care and their therapeutic outcomes, led me to Fox Chase Cancer Center, where I was able to complete my graduate training (PhD in biochemistry earned under Dr. Erica Golemis, Fox Chase Cancer Center in 2017). This made me extensively qualified in several areas of signaling dysfunction: in cancer, and in cystic kidney diseases. My primary thesis work focused on the study of cell signaling and the evaluation of novel therapies for lung cancer. As a second project, I have focused on defining how the same signaling pathways that are oncogenic in cancer can be activated, but fail to generate tumors, in the context of polycystic kidney disease. My long-term goal is to develop as a physician-scientist studying signaling pathways in cancer, with a goal of developing new treatments that target cancer cells, and generating new insights into cancer biology.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide, with a 5-year survival of only ~16%. Cytotoxic agents are currently the main class of treatment used for lung cancer: however, their effectiveness is limited because higher curative doses of these agents are associated with intolerable toxic side effects. The small molecule STA-8666 uses a novel tumor-targeting strategy, with an HSP90-binding moiety fused to SN-38 (a DNA damaging moiety that is the active metabolite of topotecan and other classic therapeutic agents). SN-38 has been shown to have high efficacy and low toxicity, associated with efficient tumor targeting in preclinical studies using patient-derived and other xenograft models for pancreatic, bladder, and small cell lung cancer. The most common causes of NSCLC in humans are somatic activating mutations in KRas gene, which occur in approximately 30% of human lung adenocarcinomas, and loss of the tumor suppressor Trp53 (60% of all cases). In our study we have used a genetically engineered murine model of NSCLC arising from induced mutation of KRas and knockout of Trp53. We have investigated whether continuous administration of STA-8666 is well-tolerated and effective in controlling the growth of early stage NSCLC, and explored the mechanism of action of STA-8666. Our data revealed that STA-8666 significantly slowed the rate of tumor growth, and was well tolerated over a four month extended dosing period. We found that STA-8666 selectively induced DNA damage and apoptosis in the tumor tissue, and reduced proliferation and phosphorylation of the proliferation-associated protein ERK1/2.
Our study indicates that STA-8666 is well tolerated over many months in young mice. While many factors go into the decision-making process for the clinical management of patients with co-morbidities or other issues that make them poor candidates for surgery, the risk of administering a drug with toxic side-effects that compromise quality of life is invariably a major concern. Efficient tumor-targeted small molecule cytotoxic therapies hold the promise of ameliorating these toxicities while improving tumor control, and could result in clinically significant improvements in both progression-free and overall survival.
A. Deneka, L. Haber, M. Kopp, A. Gaponova, A. Nikonova and E. Golemis. Tumor-targeted SN38 inhibits growth of early stage non-small cell lung cancer (NSCLC) in a KRas/p53 transgenic mouse model. PLoS One. 2017 Apr 28;12(4):e0176747. doi: 10.1371/journal.pone.0176747
A. Gaponova, A. Nikonova, A. Deneka, M. Kopp, A. Kudinov, N. Skobeleva, V. Khazak, L. Ogawa, K. Cai, K. Duncan, J. Dunkan, B. Egleston, D. Proia, Y. Boumber, E. Golemis. A Novel HSP90 Inhibitor-Drug Conjugate to SN38 Is Highly Effective in Small Cell Lung Cancer. Clinical Cancer Research. – 2016 Oct 15;22(20):5120-5129