Improved Therapeutic Window in BRCA-mutant Tumors with Antibody-linked Pyrrolobenzodiazepine Dimers with and without PARP Inhibition.

Abstract

Pyrrolobenzodiazepine dimers (PBD) form cross-links within the minor groove of DNA causing double-strand breaks (DSB). DNA repair genes such as BRCA1 and BRCA2 play important roles in homologous recombination repair of DSB. We hypothesized that PBD-based antibody-drug conjugates (ADC) will have enhanced killing of cells in which homologous recombination processes are defective by inactivation of BRCA1 or BRCA2 genes. To support this hypothesis, we found 5T4-PBD, a PBD-dimer conjugated to anti-5T4 antibody, elicited more potent antitumor activity in tumor xenografts that carry defects in DNA repair due to BRCA mutations compared with BRCA wild-type xenografts. To delineate the role of BRCA1/2 mutations in determining sensitivity to PBD, we used siRNA knockdown and isogenic BRCA1/2 knockout models to demonstrate that BRCA deficiency markedly increased cell sensitivity to PBD-based ADCs. To understand the translational potential of treating patients with BRCA deficiency using PBD-based ADCs, we conducted a "mouse clinical trial" on 23 patient-derived xenograft (PDX) models bearing mutations in BRCA1 or BRCA2 Of these PDX models, 61% to 74% had tumor stasis or regression when treated with a single dose of 0.3 mg/kg or three fractionated doses of 0.1 mg/kg of a PBD-based ADC. Furthermore, a suboptimal dose of PBD-based ADC in combination with olaparib resulted in significantly improved antitumor effects, was not associated with myelotoxicity, and was well tolerated. In conclusion, PBD-based ADC alone or in combination with a PARP inhibitor may have improved therapeutic window in patients with cancer carrying BRCA mutations.

• Authors: Haihong Zhong, Cui Chen, Ravinder Tammali, Shannon Breen, Jing Zhang, Christine Fazenbaker, Maureen Kennedy, James Conway, Brandon W Higgs, Nicholas Holoweckyj, Rajiv Raja, Jay Harper, Andrew J Pierce, Ronald Herbst, David A Tice
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 1 Pg. 89-99 (01 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 30352801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Immunological
• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human
• Immunoconjugates
• Membrane Glycoproteins
• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Pyrroles
• pyrrolo(2,1-c)(1,4)benzodiazepine
• trophoblastic glycoprotein 5T4, human
• Benzodiazepines
• olaparib

Topics

• Administration, Intravenous
• Animals
• Antineoplastic Agents, Immunological (administration & dosage, chemistry, pharmacology)
• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Benzodiazepines (chemistry)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• HeLa Cells
• Humans
• Immunoconjugates (administration & dosage, chemistry, pharmacology)
• Membrane Glycoproteins (antagonists & inhibitors)
• Mice
• Mutation
• Neoplasms, Experimental (drug therapy, genetics)
• Phthalazines (administration & dosage, pharmacology)
• Piperazines (administration & dosage, pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (administration & dosage, pharmacology)
• Pyrroles (chemistry)
• Exome Sequencing
• Xenograft Model Antitumor Assays