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Molecular Targets and Experimental Therapeutics
Program Leaders: Alex Adjei, MD, PhD and Jennifer Black, PhD
| Contact Person: | Linda M. McKernan |
Click to read the Scientific Report 2007 Overview of this program.
Click to read the entire Scientific Report 2007.
Both files are PDF documents and require Adobe Acrobat to view.
The Molecular Targets and Experimental Therapeutics Program, under the leadership of Jennifer Black, PhD and Alex Adjei, MD, PhD, seeks to discover and develop mechanism-based anticancer therapies, is being approached by (a) identifying new sites for therapeutic intervention focusing on regulation of cell cycle and apoptosis and on signal transduction, (b) investigating the mode of action of existing anticancer drugs with a view to improve their clinical utility and/or to identify new target sites, (c) delineating the basis for drug resistance to clinically useful drugs and devising circumvention strategies, (d) facilitating development of new anticancer therapies through phase I / II clinical trials, and (e) clinically validating the mode of new drug action and evaluating novel markers as response or prognostic indicators.
The Program is comprised staff from the Department of Pharmaceutical Sciences at Roswell Park, the University at Buffalo and the Hauptmann Woodward Institute for structural biology.
Thematic Organization of the Molecular Targets and Experimental Therapeutics Program
As shown the figure, the Molecular Targets and Experimental Therapeutics Program membership is arrayed into three interactive research themes: Oncogenic Signaling, Survival Responses, and Therapy Translation and Validation.
- The objective of the Oncogenic Signaling theme is to investigate oncogenic signaling pathways in search of suitable anticancer targets, to validate those targets and to devise strategies of intervention. Research focuses largely on novel cell cycle and apoptotic regulatory mechanisms and signal transduction pathways that include, EGFR signaling, Rb function, PKC signaling, ras signaling. The common hypothesis of this theme submits that cancer cells have evolved cell cycle signaling pathways and delineating these neoplastic pathways and effectors will reveal useful therapeutic targets that can be exploited via appropriately designed therapeutic or prevention strategies. In the case of over-expressed effectors, target potential is typically evaluated genetically using antisense or siRNA knock-down strategies or available inhibitor molecules. Validated targets are then pursued via various channels including collaboration with industrial partners such as Oncogene Sciences Institute (OSI) with Ron kinase targeting being one example being developed by Dr. Michael Brattain. Other investigators within this theme pursue drug action studies that focus on various signaling pathways as a means to better understand drug mechanisms while at the same time hoping to reveal alternative targets or more effective drug combinations. Examples of drugs under study include, etoposides, EGFR antagonists, MAPK inhibitors, taxanes and polyamine analogs.
- The objectives of the Survival Responses theme is to investigate mechanisms of cancer cell survival giving particular attention to inhibitors of apoptosis such as surviving and to mechanisms of drug resistance. The basic research approach hypothesizes that cancer cells have evolved cell cycle and apoptotic escape mechanisms that enable tumor develop and progression; delineating these pathways and effectors will reveal useful therapeutic targets that can be exploited via appropriately designed therapeutic or prevention strategies. As in the Oncogenic Signaling theme, a pharmacological approach hypothesizes that mechanisms of drug resistance constitute survival responses and that delineating those mechanisms and identifying means of circumventing them will have therapeutic benefit. Examples of drugs being studied in this manner include the taxanes, platinum drugs, polyamine analogs, thalidomide analogs and the proteasome inhibitor, bortezomib.
- The goal of the Therapy Translation and Validation theme is to preclinically and clinically evaluate new target-directed strategies and to validate strategy performance. Drawing on preclinical antitumor studies and toxicological studies, investigators develop innovative clinical trials of new agents and combinations. After initial indication of clinical drug action, drug combination strategies are typically used to improve drug efficacy by increasing antitumor activity, decreasing drug toxicity or both. Currently, selenomethionine is being used in this manner. Research within this theme is also focused on achieving a mechanistic understanding of these agents/combinations in the clinic through careful pharmacokinetics, pharmacodynamics and marker studies based around the targeted effector molecule.
Program Members
| Alex Adjei, MD, PhD | David W. Goodrich, PhD |
| Marina Antoch, PhD | Renuka Iyer, MD |
| Joseph Balthasar, PhD (UB) | Adam Karpf, PhD |
| Terry A. Beerman, PhD | Fengzhi Li, PhD |
| Erica Berleth, PhD | Richard Mazurchuk, PhD |
| Ralph J. Bernacki, PhD | John McGuire, PhD |
| Jennifer D. Black, PhD | Enrico Mihich, MD (Emeritus) |
| Javier Blanco, PhD | Rodney Page, DVM (Cornell) |
| Martin L. Brecher, MD | Lakshmi Pendyala, PhD |
| Asher Chanan-Khan, MD | Carl Porter, PhD |
| Patrick Creaven, MD, PhD (Emeritus) | Ashwani Rajput, MD |
| Gokul Das, PhD | Nithya Ramnath, MD |
| Huw Davies, PhD | Youcef Rustum, PhD |
| Marwan Fakih, MD | Robert Straubinger, PhD (UB) |
| Daniel Gewirth, PhD | Donald Trump, MD |
| Debashis Ghosh, PhD |
