Exploiting IR inducible NQ01 Levels Using Beta Lapachone

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant):Many cancers, such as those of the breast or prostate, have lost key programmed cell death pathways as part of their progression to a neoplastic cell. These genetic losses may include altered p53 signaling and/or deletion of caspase-mediated programmed cell death pathways. Agents that kill cells by p53-independent pathways and cause apoptosis by either bypassing deficient caspase pathways or inducing non-caspase modes of cell death are actively being sought. B-Lapachone (B-lap) and its 1,2-naphthoquinone analogs fit in this category of drugs. B-Lap is metabolized in a futile manner by human breast or prostate cancer cells expressing NAD(P)H:quinone oxidoreductase (NQO1) to deplete NAD(P)H and ATP levels and activate a calcium-dependent, non-caspase-mediated, cell death pathway that is independent of p53 status. Damage-inducible signaling and gene expression have been studied for the past 10 years. Few studies have, however, exploited damage-induced genes/enzymes for improved chemo-/radio-therapy. Drugs "activated" or "metabolized" within the cell by stress-inducible enzymes to cause lethality may be useful tools to treat specific cancers. Susceptible cancers would up-regulate these enzymes after clinically relevant doses of ionizing radiation (IR). A biopsy screen of such tumors could reveal their potential sensitivities to drugs that "metabolically kill" cancer cells through stress-inducible enzymes. We hypothesize that B-lap is such a compound. This drug is metabolized by NQO1 (a.k.a., Dl diaphorase or x-ray-inducible transcript/protein #3, xip3) in a futile manner to cause apoptosis. To test our hypothesis, we will use human breast or prostate cancer cells that constitutively o. conditionally express, or are deficient in expression of, NQO 1. Cell lines or xenografts from cell lines that dramatically up-regulate NQO1 after JR will also be used in combination with the NQO1 inhibitor, dicoumarol, to examine B-lap-mediated radiosensitization. Studies in vitro and in vivo will be performed using the above breast or prostate cancer cell lines/xenografts to show that IR-inducible NQO 1 levels are required for radiosensitization by B-lap. A small cohort of B-lap analogs will also be tested to find better compounds for preclinical trails in vivo. Pre-clinical studies of B-lap, and a one or two synthetic derivatives, using athymic nude mice bearing human breast and prostate cancer xenografts, expressing or no expressing NQO 1, will be performed to develop this novel agent for future Phase I studies.