Yanis Boumber, MD, PhD
Office Phone: (215) 728-3135
Tumor Drivers and New Treatments in Lung Cancer
Non-small cell lung cancer remains the deadliest of cancers, and despite many advances in therapeutic management, the five-year survival rate this disease remains very low. The long-term goal of my laboratory is to establish an expertise in translational research addressing lung cancer biology and the treatment of thoracic malignancies.
Part of our research focuses on the role of Musashi-2 (Msi2) in non-small cell lung cancer. The Musashi family of RNA-binding protein regulates mRNA translation to control numerous cancer-related signaling processes. Our preliminary studies for the first time identified Msi2 as an oncogene driving lung cancer progression. We are using mouse models, human cell lines, and analysis of primary tumor samples to define to function of Msi2. The goal of this work is to obtain a better understanding of the events contributing to lung cancer progression, with the anticipation that this knowledge will support more effective use of targeted and cytotoxic therapies in the clinical setting.
Another important focus of the laboratory is small cell lung cancer (SCLC). This is an aggressive and deadly disease, with essentially no effective treatments, no new drugs approved in recent decades, and no targeted agents in existence. We are currently evaluating a new class of drugs developed by Synta Pharmaceuticals which use anticancer drugs conjugated to an HSP90–binding moiety as a novel way to deliver anticancer agents directly to tumors. In the lab, we focused on pre-clinical safety and efficacy and mechanistic studies of this new compound in cell lines and in mice. The proposed study could be a step forward to development of future effective treatment strategies for small cell lung cancer patients.
Musashi-2 Regulates The Aggressiveness of Non-Small Cell Lung CancerIn collaboration with Erica Golemis
The Musashi-2 project originated in the analysis of highly metastatic versus less metastatic lung cancers emerging in a KRAS/p53 mutated mouse model of lung cancer, developed by Jon Kurie and Guillermina Lozano at MD Anderson. Msi2 is an RNA-binding protein that regulates mRNA translation, and has previously been shown to have dysregulated function in leukemias and a small number of other cancers, with specific mRNAs relevant to cell cycle control and differentiation status defined as important direct targets. We identified Msi2 upregulation as common in the more metastatic cells derived from mouse tumors, and showed that loss of Msi2 suppressed proliferation, decreased invasion and metastasis, increased apoptosis, and increased aneuploidy. We have now generated an extensive body of preliminary data demonstrating that knockdown of human Musashi-2 (MSI2) also significantly reduces tumorigenicity and reprograms cell signaling in human primary tumors and cell line models for NSCLC. The Musashi proteins have been not well studied in lung cancer. We hope these studies of Msi2 will lead eventually lead us to improved treatment strategies of this difficult cancer.Top
HDC-SN38 Conjugate for Treatment of Small Cell Lung CancerIn collaboration with Erica Golemis, David Proia, Hossein Borghaei & James Duncan
HSP90 is an attractive therapeutic target in small cell lung cancer (SCLC) and other tumors, based on its extreme elevation and activation in tumors growing in stressful microenvironments. Synta Pharmaceuticals, the developers of the Hsp90 inhibitor ganetespib, has recently developed several HSP90-Inhibitor drug conjugates. HSP90-binding small molecules have been shown to accumulate specifically in tumors, as opposed to their rapid clearance in normal tissues. Synta has designed a system to conjugate anticancer drugs to HSP90-binding small molecules as a novel way to deliver anticancer agents directly to tumors. Synta’s lead compound, HDC-SN38, is a conjugate of an HSP90 inhibitor with SN38, the active metabolite of irinotecan, which is successfully used in small cell lung cancer. We hypothesize that HDC SN-38 would be a highly effective therapy in both frontline and salvage settings for treating patients with small cell lung cancer. Testing of the compound is in progress in vivo and in vitro, along with mechanistic studies to identify biomarkers of response. Besides testing novel compounds, we also are using the research data to generate concepts for testing in the clinical trials, using HDC-SN38 both in the salvage and frontline settings in SCLC, with the goal of developing feffective treatment strategies for patients with this disease.Top