Summary Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen consumption rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small cell lung, pancreatic and breast, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.

Dose escalation to 50 Gy has been completed without DLT. A multicenter phase II trial is underway treating patients to 50 Gy in five fractions to further evaluate this experimental therapy.

Purpose Inhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers including glioblastomas (GBM), which are extremely radio- and chemo-resistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating GBM. Our lab has previously demonstrated that the dual PI3K/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-PKcs and ATM, in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemo-sensitizer in pre-clinical mouse GBM models. Experimental design The radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic GBM models. Tumors were generated using the radioresistant U87-vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation (IR) and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth. Results NVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of IR-induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice. Notably, tumors displayed a higher DSB-load when compared to normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with IR for the treatment of GBM. Conclusions These results demonstrate that it may be possible to significantly improve GBM therapy by combining IR with potent and bioavailable DNA repair inhibitors like NVP-BEZ235.

Purpose Pancreatic cancer is the fourth leading cause of cancer-related deaths, in which the 5-year survival rate is less than 5%. Current standard of care therapies offer little selectivity and high toxicity. Novel, tumor-selective approaches are desperately needed. Although prior work suggested that β-lapachone (β-lap) could be used for the treatment of pancreatic cancers, the lack of knowledge of the compound’s mechanism of action prevented optimal use of this agent. Experimental Design We examined the role of NAD(P)H:quinone oxidoreductase-1 (NQO1) in β-lap–mediated antitumor activity, using a series of MIA PaCa-2 pancreatic cancer clones varying in NQO1 levels by stable shRNA knockdown. The antitumor efficacy of β-lap was determined using an optimal hydroxypropyl-β-cyclodextran (HPβ-CD) vehicle formulation in metastatic pancreatic cancer models. Results β-lap–mediated cell death required ~90 enzymatic units of NQO1. Essential downstream mediators of lethality were as follows: (i) reactive oxygen species (ROS); (ii) single-strand DNA breaks induced by ROS; (iii) poly(ADP-ribose)polymerase-1 (PARP1) hyperactivation; (iv) dramatic NAD+/ATP depletion; and (v) programmed necrosis. We showed that 1 regimen of β-lap therapy (5 treatments every other day) efficaciously regressed and reduced human pancreatic tumor burden and dramatically extended the survival of athymic mice, using metastatic pancreatic cancer models. Conclusions Because NQO1 enzyme activities are easily measured and commonly overexpressed (i.e., >70%) in pancreatic cancers 5- to 10-fold above normal tissue, strategies using β-lap to efficaciously treat pancreatic cancers are indicated. On the basis of optimal drug formulation and efficacious antitumor efficacy, such a therapy should be extremely safe and not accompanied with normal tissue toxicity or hemolytic anemia.