Z01 BC 010716 (Z01) | |||
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Title | Phase I/II study of BCL-family inhibitors in lymphoma | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Wilson, Wyndham | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $57,991 | Project Dates | 10/01/2006 - N/A |
Fiscal Year | 2007 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
N/A |
Hodgkins Disease (10.0%) Non Hodgkins Lymphoma (30.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Systemic Therapies - Clinical Applications |
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Abstract | |||
The Bcl-2 family proteins are important regulators of the intrinsic apoptosis pathway. The Bcl-2 oncogene was first identified in follicular lymphoma where the t(14;18) chromosomal translocation results in significant over-expression of the protein in B-cells. In contrast to other known oncogenes, Bcl-2 does not stimulate cellular proliferation, but rather inhibits programmed cell death by protecting cells from a wide variety of pro apoptotic stimuli, including cytokine withdrawal, irradiation, cytotoxic drugs, heat and deregulated oncogenes.1 The Bcl-2 family of genes encodes a family of closely related proteins that possess either pro apoptotic or anti-apoptotic activity and share up to four Bcl-2 Homology (BH) domains.2,3,4,5 The anti-apoptotic family members (Bcl-XL, Bcl-2, Bcl-w, Bcl-B, A1 and Mcl 1) are characterized by four BH domains that are designated BH1-4. The pro apoptotic family members can be further subdivided into multidomain proteins (Bax, Bak) and the BH3-only proteins (Bad, Bik, Bid, Bim Hrk, Bmf, Noxa, Puma). The interplay between these three groups of proteins serves as the gateway to the intrinsic apoptosis pathway. ABT-263 is a novel small molecule Bcl-2 family protein inhibitor that binds with high affinity (Ki  1 nM) to multiple anti-apoptotic Bcl-2 family proteins including Bcl-XL, Bcl-2, Bcl-w, and Bcl-B. ABT-263 displays potent mechanism-based cytotoxicity (EC50  1 M) against human tumor cell lines derived from small cell lung carcinomas and lymphoid malignancies. ABT-263 exhibits potent single agent activity against 10 of 22 cell lines consisting of multiple leukemia and lymphoma types spanning both B-cell and T-cell malignancies. In two flank models of diffuse large B-cell lymphoma (DoHH-2 and WSU-DLCL2), significant monotherapy activity was noted when ABT-263 was administered at a dose of 100 mg/kg/day given p.o., q.d.  17 days. Both of these tumors are known to express high levels of Bcl-2 due to the t(14;18) translocation. The WSU-DLCL2 line was isolated from a patient whose disease progressed following chemotherapy, radiation therapy and bone marrow transplantation and is recognized as a model of therapy-resistant lymphoma. |