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.

The clinical experimental agent, β-lapachone (β-lap; Arq 501), can act as a potent radiosensitizer in vitro through an unknown mechanism. In this study, we analyzed the mechanism to determine whether β-lap may warrant clinical evaluation as a radiosensitizer. β-Lap killed prostate cancer cells by NAD(P)H:quinone oxidoreductase 1 (NQO1) metabolic bioactivation, triggering a massive induction of reactive oxygen species, irreversible DNA single-strand breaks (SSB), poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, NAD + /ATP depletion, and μ-calpain-induced programmed necrosis. In combination with ionizing radiation (IR), β-lap radiosensitized NQO1 + prostate cancer cells under conditions where nontoxic doses of either agent alone achieved threshold levels of SSBs required for hyperactivation of PARP-1. Combination therapy significantly elevated SSB level, γ-H2AX foci formation, and poly(ADP-ribosylation) of PARP-1, which were associated with ATP loss and induction of μ-calpain-induced programmed cell death. Radiosensitization by β-lap was blocked by the NQO1 inhibitor dicoumarol or the PARP-1 inhibitor DPQ. In a mouse xenograft model of prostate cancer, β-lap synergized with IR to promote antitumor efficacy. NQO1 levels were elevated in ∼60% of human prostate tumors evaluated relative to adjacent normal tissue, where β-lap might be efficacious alone or in combination with radiation. Our findings offer a rationale for the clinical utilization of β-lap (Arq 501) as a radiosensitizer in prostate cancers that overexpress NQO1, offering a potentially synergistic targeting strategy to exploit PARP-1 hyperactivation. Cancer Res; 70(20); 8088-96. ©2010 AACR.

Tumours frequently activate genes whose expression is otherwise biased to the testis, collectively known as cancer–testis antigens (CTAs). The extent to which CTA expression represents epiphenomena or confers tumorigenic traits is unknown. In this study, to address this, we implemented a multidimensional functional genomics approach that incorporates 7 different phenotypic assays in 11 distinct disease settings. We identify 26 CTAs that are essential for tumor cell viability and/or are pathological drivers of HIF, WNT or TGFβ signalling. In particular, we discover that Foetal and Adult Testis Expressed 1 (FATE1) is a key survival factor in multiple oncogenic backgrounds. FATE1 prevents the accumulation of the stress-sensing BH3-only protein, BCL-2-Interacting Killer (BIK), thereby permitting viability in the presence of toxic stimuli. Furthermore, ZNF165 promotes TGFβ signalling by directly suppressing the expression of negative feedback regulatory pathways. This action is essential for the survival of triple negative breast cancer cells in vitro and in vivo. Thus, CTAs make significant direct contributions to tumour biology.

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Introduction Lung cancer diagnostic and treatment delays have been described for several patient populations. However, few studies have analyzed these intervals among patients treated in contemporary health care systems in the United States. We therefore studied the timing of lung cancer diagnosis and treatment at a U.S. medical center providing care to a diverse patient population within two different hospital systems. Methods We performed a retrospective analysis of consecutive patients diagnosed with non-small cell lung cancer stages I–III from 2000 to 2005 at public and private hospitals affiliated with the University of Texas Southwestern Medical Center. We recorded patient and disease characteristics; dates of initial radiograph suspicious for lung cancer, diagnosis, and treatment; and overall survival. Associations between these factors were assessed using univariate analysis, multivariate logistic regression, and Kaplan-Meier survival analysis. Results A total of 482 patients met criteria for analysis. In univariate analyses, the image-treatment interval was significantly associated with race, age, income, insurance type, and hospital type (76 days for public versus 45 days for private; P<0.0001). In multivariate analysis, only hospital type remained significantly associated with the image-treatment interval; patients in the private hospital setting were more likely to receive timely treatment (HR 1.85; 95% CI, 1.37–2.50; P<0.001). In univariate analysis, the image-treatment interval was not associated with disease stage (P=0.27) or with survival (P=0.42). Conclusion Intervals between suspicion, diagnosis, and treatment of lung cancer vary widely among patients. Health care system factors, such as hospital type, largely account for these discrepancies. In this study, these intervals do not appear associated with clinical outcomes.