Recent phase I studies have reported single-agent activities of poly （ADP-ribose） polymerase （PARP） inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate...Recent phase I studies have reported single-agent activities of poly （ADP-ribose） polymerase （PARP） inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate cancer, ETS gene rearrangement and loss of PTEN, have been linked to increased sensitivity to PARP inhibitor in preclinical models. Emerging evidence also suggests that PARP1 plays an important role in mediating the transcriptional activities of androgen receptor （AR） and ETS gene rearrangement. In this article, the preclinical work and early-phase clinical trials in developing PARP inhibitor-based therapy as a new treatment paradigm for metastatic prostate cancer are reviewed.展开更多
Most patients with multiple myeloma (MM) respond well to initial therapy, but invariably relapse due to evolution of resistant phenotypes. Here we examine the evolutionary dynamics of proliferation of resistant MM phe...Most patients with multiple myeloma (MM) respond well to initial therapy, but invariably relapse due to evolution of resistant phenotypes. Here we examine the evolutionary dynamics of proliferation of resistant MM phenotypes during therapy. By applying computational models to data from three clinical trials for newly diagnosed MM patients, we have quantified the size and level of chemoresistance of subpopulations within the tumor burden in 124 patients, prior to and during therapy. Subsequently, we used the computational models to explore an alternative strategy of “adaptive therapy” (AT), which includes defined treatment holidays, to improve the duration of “controlled disease” (CD). Simulations showed that AT could prolong CD in all three trials: 50.0% vs. 11.1% 50-month CD for a single agent approach in older adults (P = 0.0123), 80.4% vs. 58.8% 60-month CD for a multi-agent bortezomib based therapy (P = 0.0082), and 54.0% vs. 24.0% 60-month CD for a multi-agent lenalidomide based therapy (P < 0.0001). Increases in duration of CD resulted from the stabilization of tumor burden, which in turn would delay the growth of chemoresistant sub-populations in patients with partial (PR), or very good partial response (VGPR). These computational algorithms suggest that AT may provide an alternative and feasible therapeutic management strategy in MM.展开更多
文摘Recent phase I studies have reported single-agent activities of poly （ADP-ribose） polymerase （PARP） inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate cancer, ETS gene rearrangement and loss of PTEN, have been linked to increased sensitivity to PARP inhibitor in preclinical models. Emerging evidence also suggests that PARP1 plays an important role in mediating the transcriptional activities of androgen receptor （AR） and ETS gene rearrangement. In this article, the preclinical work and early-phase clinical trials in developing PARP inhibitor-based therapy as a new treatment paradigm for metastatic prostate cancer are reviewed.
文摘Most patients with multiple myeloma (MM) respond well to initial therapy, but invariably relapse due to evolution of resistant phenotypes. Here we examine the evolutionary dynamics of proliferation of resistant MM phenotypes during therapy. By applying computational models to data from three clinical trials for newly diagnosed MM patients, we have quantified the size and level of chemoresistance of subpopulations within the tumor burden in 124 patients, prior to and during therapy. Subsequently, we used the computational models to explore an alternative strategy of “adaptive therapy” (AT), which includes defined treatment holidays, to improve the duration of “controlled disease” (CD). Simulations showed that AT could prolong CD in all three trials: 50.0% vs. 11.1% 50-month CD for a single agent approach in older adults (P = 0.0123), 80.4% vs. 58.8% 60-month CD for a multi-agent bortezomib based therapy (P = 0.0082), and 54.0% vs. 24.0% 60-month CD for a multi-agent lenalidomide based therapy (P < 0.0001). Increases in duration of CD resulted from the stabilization of tumor burden, which in turn would delay the growth of chemoresistant sub-populations in patients with partial (PR), or very good partial response (VGPR). These computational algorithms suggest that AT may provide an alternative and feasible therapeutic management strategy in MM.
