Development of Mechanism-Based Stratgies for CLL Therapy

$252,101P01FY2008CANIH

University Of California, San Diego, La Jolla CA

Investigators

Linked publications & trials

Paper 35230971 Paper 34686499 Paper 34285341 Paper 33714981 Paper 33689703 Paper 33627156 Paper 33615197 Paper 33604581 Paper 33451349 Paper 33081820 Paper 31723042 Paper 31543463 Paper 31292113 Paper 31204237 Paper 31142838 Paper 30967392 Paper 30923040 Paper 30821551 Paper 30712845 Paper 30622177 Paper 30575108 Paper 30568170 Paper 30503705 Paper 30282833 Paper 30242085 Paper 29880603 Paper 29872501 Paper 29859176 Paper 29752258 Paper 29678828 Paper 29263891 Paper 28972595 Paper 28971726 Paper 28923920 Paper 28835371 Paper 28737232 Paper 28526063 Paper 28515090 Paper 28491097 Paper 28465529 Paper 28465528 Paper 28412730 Paper 28388280 Paper 28371109 Paper 28187444 Paper 28179635 Paper 28115735 Paper 28102226 Paper 28095146 Paper 28089635 Paper 28077600 Paper 28034907 Paper 28026162 Paper 28017967 Paper 27909343 Paper 27904138 Paper 27903679 Paper 27890934 Paper 27870563 Paper 27861736 Paper 27818134 Paper 27815263 Paper 27797975 Paper 27776107 Paper 27766619 Paper 27756747 Paper 27750279 Paper 27742074 Paper 27742068 Paper 27721895 Paper 27677095 Paper 27660167 Paper 27655665 Paper 27653691 Paper 27650502 Paper 27588518 Paper 27534555 Paper 27527866 Paper 27499047 Paper 27480113 Paper 27434128 Paper 27389174 Paper 27378086 Paper 27352257 Paper 27351634 Paper 27311839 Paper 27298257 Paper 27247136 Paper 27230687 Paper 27223062 Paper 27213184 Paper 27182988 Paper 27144715 Paper 27118540 Paper 27117452 Paper 27096594 Paper 27076684 Paper 27071132 Paper 27065330 Paper 27058259

Abstract

The goals of this project are to develop in the laboratory, using model systems and primary CLL cells in vitro[unreadable] an understanding of the mechanisms of action of anticancer agents acting alone and in mechanism-based[unreadable] combinations. This knowledge base will provide rationales for the design and evaluation of clinical trials that[unreadable] will test hypotheses regarding the actions and interactions of these agents in CLL cells in patients during[unreadable] therapy. Thus, the central hypothesis we will test is that knowledge derived from an understanding of the[unreadable] metabolism, mechanisms of action, and the interactions of new anticancer therapeutics can be used to[unreadable] design and evaluate novel therapeutic regimens for the treatment of patients with CLL. To achieve these[unreadable] goals, we will address the following questions: 1. Do nucleoside analogs with novel actions provide[unreadable] pharmacological and clinical advantages over fludarabine for the treatment of B-CLL? Our focus here will be[unreadable] on the new nucleoside analog, clofarabine which has pharmacologic properties different from fludarabine. 2.[unreadable] Can strategies to reduce survival proteins selectively kill CLL cells? We are developing 8-chloro-adenosine[unreadable] ribonucleotide analog that reduces cellular bioenergy and blocks transcription. Also, we will evaluate the[unreadable] transcription-directed actions of flavopiridol. The actions of each of these agents decreases anti-apoptotic[unreadable] proteins in CLL cells. 3. Will mechanism-based combinations of cytotoxic agents improve outcome in CLL[unreadable] patients? The cellular responses to inhibition of excision DNA repair processes will be investigated in CLL[unreadable] cells, and extended to new DNA damaging agents and drugs that inhibit DNA repair. 4. Can orsaponin, a[unreadable] synthetic natural compound with potent anticancer activity and unique mechanism of action, be used as a[unreadable] novel agent for treatment of CLL? The action mechanism(s) of this novel agent that selectively kills CLL[unreadable] cells independent of p53 status will be investigated in preparation for clinical development. Interactions with[unreadable] other projects in this program will strengthen our investigations.

View original record on NIH RePORTER →