Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences i...Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences in clinical trial design have contributed to distinct indications for each of the PARP inhibitors. Toxicity patterns are also emerging that suggest agents differ in their normal tissue tolerance - beyond what might be expected by dose variations and/or exposure to prior treatment. PARP inhibitor resistance is an increasingly relevant issue as the drugs move to the forefront of advanced ovarian/breast cancer treatment, and is an active area of ongoing research. This review examines the PARP inhibitor clinical trials that have led to approved indications in ovarian and breast cancers, PARP inhibitor targets and pharmacological differences between the PARP inhibitors, emerging mechanisms of resistance, and key clinical questions for future development.展开更多
Intraperitoneal(IP)delivery of cisplatin was developed in the 1970s based on a strong pharmacologic rationale and rodent models.Its advantage over intravenous(IV)administration was supported initially by observational...Intraperitoneal(IP)delivery of cisplatin was developed in the 1970s based on a strong pharmacologic rationale and rodent models.Its advantage over intravenous(IV)administration was supported initially by observational studies in treating recurrent ovarian cancer and eventually by better outcomes from IP vs.IV cisplatin in randomized studies in patients undergoing optimal surgical debulking at diagnosis.In the past two decades,with the introduction of novel anticancer interventions(such as taxanes,bevacizumab,inhibitors of DNA repair,and immune check point inhibitors),advantages of IP drug delivery are less clear and concerns are raised on cisplatin's therapeutic index.The discovery of BRCA genes and their key role in DNA repair,on the other hand,have strengthened the rationale for IP drug delivery:high grade serous cancers arising in the Mullerian epithelium in association with hereditary or somatic BRCA function inactivation are linked to peritoneal spread of cells that-while initially sensitive-are prone to emergence of platinum resistance.Therefore,selection of patients based on genomic features and focusing on the better tolerated IP carboplatin are ongoing.Recent examples of leveraging the peritoneal route include(1)targeting the cell membrane copper transport receptor-that is shared by platinums-by the combination of the proteasome inhibitor bortezomib and IP carboplatin;and(2)enhancing IP 5-fluoro-2-deoxyuridine cytotoxicity when coupled with PARP inhibition.展开更多
文摘Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences in clinical trial design have contributed to distinct indications for each of the PARP inhibitors. Toxicity patterns are also emerging that suggest agents differ in their normal tissue tolerance - beyond what might be expected by dose variations and/or exposure to prior treatment. PARP inhibitor resistance is an increasingly relevant issue as the drugs move to the forefront of advanced ovarian/breast cancer treatment, and is an active area of ongoing research. This review examines the PARP inhibitor clinical trials that have led to approved indications in ovarian and breast cancers, PARP inhibitor targets and pharmacological differences between the PARP inhibitors, emerging mechanisms of resistance, and key clinical questions for future development.
文摘Intraperitoneal(IP)delivery of cisplatin was developed in the 1970s based on a strong pharmacologic rationale and rodent models.Its advantage over intravenous(IV)administration was supported initially by observational studies in treating recurrent ovarian cancer and eventually by better outcomes from IP vs.IV cisplatin in randomized studies in patients undergoing optimal surgical debulking at diagnosis.In the past two decades,with the introduction of novel anticancer interventions(such as taxanes,bevacizumab,inhibitors of DNA repair,and immune check point inhibitors),advantages of IP drug delivery are less clear and concerns are raised on cisplatin's therapeutic index.The discovery of BRCA genes and their key role in DNA repair,on the other hand,have strengthened the rationale for IP drug delivery:high grade serous cancers arising in the Mullerian epithelium in association with hereditary or somatic BRCA function inactivation are linked to peritoneal spread of cells that-while initially sensitive-are prone to emergence of platinum resistance.Therefore,selection of patients based on genomic features and focusing on the better tolerated IP carboplatin are ongoing.Recent examples of leveraging the peritoneal route include(1)targeting the cell membrane copper transport receptor-that is shared by platinums-by the combination of the proteasome inhibitor bortezomib and IP carboplatin;and(2)enhancing IP 5-fluoro-2-deoxyuridine cytotoxicity when coupled with PARP inhibition.
