Abstract
Platinum drugs are the frontline therapy in many carcinomas, including high-grade serous ovarian cancers. Clinically, high-grade serous carcinomas have an apparent complete response to carboplatin, but tumors invariably recur and response to platinum drugs diminishes over time. Standard of care prohibits re-administration of platinum drugs to these patients who are labeled as having platinum-resistant disease. In this stage patients are treated with non-platinum agents and outcomes are often poor. In vivo and in vitro data presented here demonstrate that this clinical dogma should be challenged. Platinum drugs can be an effective therapy even for platinum-resistant carcinomas as long as they are combined with an agent that specifically targets mechanisms of platinum resistance exploited by the therapy-resistant tumor subpopulations. High levels of cellular inhibitor of apoptosis proteins cIAP1 and 2 (cIAP) were detected in up to 50% of high-grade serous and non-high-grade serous platinum-resistant carcinomas. cIAP proteins can induce platinum resistance and they are effectively degraded with the drug birinapant. In platinum-resistant tumors with ≥22.4 ng of cIAP per 20 µg of tumor lysate, the combination of birinapant with carboplatin was effective in eliminating the cancer. Our findings provide a new personalized therapeutic option for patients with platinum-resistant carcinomas. The efficacy of birinapant in combination with carboplatin should be tested in high-grade serous carcinoma patients in a clinical trial.
Highlights
Platinum drugs were discovered in 1965 by Barnett Rosenberg,[1] and were fast-tracked through the NIH for the treatment of cancers
We have previously shown that high levels of cIAP1 and 2 (cIAP) proteins in the CA125 negative cancer-initiating cells of chemo-naive primary patient High-grade serous carcinomas (HGSCs) specimens induces platinum resistance.[12]
C had previously found that a mechanism inducing platinum resistance in HGSCs is evasion of apoptosis mediated by high
Summary
Platinum drugs were discovered in 1965 by Barnett Rosenberg,[1] and were fast-tracked through the NIH for the treatment of cancers. To estimate the frequency of a therapeutic response to birinapant and carboplatin co-therapy, its efficacy was tested in a cohort of 23 primary patient HGSC samples (15 chemo-naive, 1 recurrent platinum-sensitive, 5 platinum resistant and 2 neoadjuvant (Fig. 1b). A Assessment of cell survival after drug treatment in the in vitro organoid bioassay (n = 3 replicates/specimen) revealed that in a cohort of 23 randomly selected primary patient HGSC specimens 13 were sensitive to co-therapy, while 10 were resistant. D Analysis of all platinum-resistant samples (HGSC and non-HGSC) demonstrates that cIAP levels in unfractionated or vehicle-treated tumor cells can segregate co-therapy sensitive (n = 9) vs co-therapy resistant (n = 10) carcinomas in clinically defined platinum-resistant disease By combining carboplatin with birinapant, long-term remissions were achieved in physiologic disease models (Fig. 4b), a response that could be predicted using the in vitro organoid bioassay
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