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gdpawel · 10-18-2011, 04:07 PM

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.

10-18-2011, 04:07 PM	#5
gdpawel Senior Member Join Date: Aug 2006 Location: Pennsylvania Posts: 1,080	Functional Analysis of PARP Inhibitors in Human Tumor Primary Cultures 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.