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PARP Inhibitors for Melanoma?

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Patients with melanoma are now candidates for the antibody Yervoy (ipilimumab) and/or the B-Raf inhibitor PLX4720. The latter requires identification of a V600E b-RAF mutation. It would seem appropriate for patients to be given insights on those options. The problem in cell function analysis, is that Ipilimumab effects are modest and PLX responses are generally short-lived.

Some cell-based assay labs have explored the biology of PARP inhibitors, alone and in combination, in actual human tumor primary culture microspeheroids (microclusters), in breast, ovarian and other cancers. In these investigations, the lab applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations. As seen with PARP inhibitors, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

The Sunday, April 3, 2011, experimental and molecular therapeutics poster session at the American Association for Cancer Research (AACR) 102nd annual meeting included Dr. Robert Nagourney's Rational Therapeutics presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors he explored the activities, synergies and possible clinical utilities of these novel compounds.

The results of functional analysis with the mTOR/P13K and MEK/ERK inhibitors, BEZ235 and AZD6244, alone and in combination in human tumor primary culture microspheroids (microclusters): Exploration of horizontal pathway targeting. While the profiles of each drug alone are of interest, the profiles of the drugs in combination are better still.

The phenomenon of cross-talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When clinical therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies. This is what has been observed with these duel inhibitor combinations. What is interesting is the fact that the activities cut across tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear.

Moreover, cancers share pathways across tumor types, pathways that might not intuitively seem related. This is the beauty of cell-based functional profiling platform. It allows the exploration of drugs and combinations that most oncologists wouldn’t think of. It is these counterintuitive explorations that will likely lead to meaningful advances.

The findings were instructive. First, it saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform (functional profiling). Second, it saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with expectations. After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that his lab blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

Functional profiling measures biological signals rather than DNA indicators, which plays an important role in cancer drug selection and is demonstrably greater and more compelling data currently generated from DNA analyses. The results of their investigation support the clinical relevance of targeting the MEK/ERK and PI3K/mTOR pathways and more importantly, suggest "dual" pathway inhibition (horizontal) to be a productive strategy for further clinical development. Disease specific profiles and sequence dependence are explored and reported.

PARP is a very active enzyme involved in the repair of single-strand breaks in DNA or modified bases. It binds to DNA damage and adds multiple sugar molecules to the DNA that act as a beacon to recruit other components of DNA repair.

Emerging work on assays (PARP levels correlating with response to PARP inhibitors) have shown pretty good response with PARP inhibitors as single agents and some results combining the PARP inhbitors with mustard alkylators, platins and drug combinations to optimize PARP inhibitor combinations. These results, though exploratory, suggest a superior approach for drug development, allowing the lab to identify important leads much faster than the clinical trial process.

Source: Robert A. Nagourney, Paula Bernard, Federico Francisco, Ryan Wexler, Steve Evans, Rational Therapeutics, Long Beach, CA. Proceedings of AACR - Volume 52 - April 2011.

Poster from Rational Therapeutics Session at 2011 AACR Meeting

http://robertanagourney.wordpress.com/2011/04/28/poster-from-rational-therapeutics-session-at-2011-aacr-meeting/

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Poly ADP ribose polymerase (PARP) is a nuclear enzyme associated with response to DNA damage. Following single strand DNA breaks, the enzyme attaches a backbone of ADP and ribose that serves to initiate DNA repair. Certain classes of chemotherapeutics, specifically alkylating agents, can induce injury that results in extensive poly ADP ribosylation resulting in the exhaustion of intercellular pools of NAD and ATP ultimately leading to cell death.

Although PARP inhibitors have recently entered the clinical cancer literature mostly relating to the treatment of BRCA+ and triple negative patients, neither PARP nor PARP inhibitors are new to the cancer researcher community, according to Dr. Robert Nagourney, medical director at Rational Therapeutics, one of the pioneers of the functional profiling technique.

His group first became interested following a 1988 study by Distelhorst from Case Western Reserve (Distelhorst CW, Blood 1988 Oct;72(4):1305-09) that described a mechanism of cell death that correlated with their work in childhood leukemia. Previously, investigators at Scripps Clinic had described PARP’s role in response to 2CDA (Seto, S., et al. J Clin. Invest. 1985 Feb;75(2):377-83). His group has studied small molecule inhibitors of PARP for many years, and more recently, they have expanded these investigations to include BSI201 (iniparib) and AZD2281 (olaparib). Both of which are undergoing clinical investigations. Nagourney will be reporting their findings with these PARP inhibitors at the 2011 ASCO meeting (Nagourney, R., et al Proceedings Amer Soc Clin Oncol. 2011).

PARP inhibitors are easily studied and provide interesting signals in the tissue studied. They have seen activity in BRCA+ patients and some triple negative breast cancers. They have also identified synergy with other classes of drugs. The compounds are a welcome addition to the cancer therapy armamentarium and continue to be actively studied in the cell-based functional profiling platform.

Of interest is the recent failure of the iniparib plus Carboplatin & gemcitabine Phase III trial to meet progression-free and overall survival goals in triple negative breast cancer patients (Zacks Investment Research on January 31, 2011). This failure may reflect the need to apply predictive methodologies to select candidates for these drugs, similar to Nagourney's successful work with other classes of compounds.

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Functional analysis of PARP inhibitors AZD 2281 and BSI-201 in human tumor primary cultures: A comparison of activity and examination of synergy with cytotoxic drugs.

Sub-category: DNA Repair and Apoptosis

Category: Developmental Therapeutics - Experimental Therapeutics

Meeting: 2011 ASCO Annual Meeting

Abstract No: e13599

Citation: J Clin Oncol 29: 2011 (suppl; abstr e13599)

Author(s): R. A. Nagourney, K. R. Kenyon, F. R. Francisco, P. J. Bernard, S. S. Evans; Rational Therapeutics, Long Beach, CA

Abstract:

Background:

Poly (ADP-ribose) polymerases (PARP) are activated in response to cellular injury. DNA damage from radiation and cytotoxic drugs results in the up-regulation of PARP 1/2, leading to base excision repair. PARP inhibition enhances chemotherapy and induces cell death by synthetic lethality in patients with deficient homologous repair (BRCA1/2 and ATM). PARP inhibitors in development include benzamides, phthalazinones and benzimidazoles. Our work with 3-aminobenzamide (3-AB) led to the study of BSI-201 and AZD 2281, in human tumor micro-spheroids, isolated from surgical specimens and cytologically (+) fluids.

Methods:

Delayed loss of membrane integrity, morphologic and metabolic measures of drug-induced programmed cell death (EVA/PCD) were applied in 45 human tumor specimens exposed to PARP inhibitors, alone and in combination with cytotoxics. Lethal concentrations (LC50) were interpolated from 5-point dose response curves. Synergy was assessed by median effect. Drug activity comparisons were performed by modified Z-score.

Results:

PARP inhibitors are active in human tumor micro-spheroids. Activities for AZD 2281 and BSI-201 are superior to 3AB favoring BRCA1/2 and triple-negative (TN) breast over wild type and ER/PR (+); (AZD avg LC50 12 vs. 60 ug/mL; BSI avg LC50 19 vs. 30 ug/mL). AZD2281 and BSI-201 reveal synergy with CDDP, CDDP and gemcitabine, and alkylators. Of interest, BSI-201 and AZD-2281 activity did not correlate in parallel analyses (Pearson Moment, r = 0.07, P > 0.5). A comparison of BSI-201 and AZD 2281 activity with CDDP or taxol, suggested correlation with CCDP but not with taxol.

Conclusions:

1) PARP inhibitors are active in human tumors favoring BRCA1/2 and TN breast. 2) Favorable interactions with DNA damaging agents are observed. 3) Activity profiles correlate more strongly with CDDP than taxol. 4) Direct comparisons suggest somewhat different activity profiles for BSI-201 vs. AZD-2281. 5) Individual activity/synergy profiles may provide opportunities for patient selection in the development of novel PARP combinations. Analyses in BRCA 1/2 and TN breast cancers are ongoing.

Supported by The Vanguard Cancer Foundation and The Nagourney Institute.

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