Platinum-resistant Carcinoma Research Articles

Retraction Note: Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy

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. Carboplatin efficacy can be restored by administering it with birinapant, a drug combination that targets platinum-resistant cancer cells. Platinum-based chemotherapeutics are used to treat almost 50% of cancer patients. Despite excellent initial response rates, tumor growth recurs in most patients as they develop resistance to therapy. Sanaz Memarzadeh and colleagues at the University of California, Los Angeles, show that the addition of birinapant to carboplatin eliminates platinum-resistant ovarian cancer cells by degrading the cell death-inhibiting proteins cIAP1 and cIAP2. Carboplatin and birinapant co-therapy restored the efficacy of the chemotherapeutic in human tumor samples and in mice with platinum-resistant tumors. Furthermore, the levels of cIAP protein in the resistant cells were predictive of the therapeutic response. These findings will help to select clinical trial patients that are most likely to benefit from this combination therapy.

Bevacizumab and capecitabine in relapsed platinum-resistant epithelial carcinoma of ovary: A retrospective study

Background: Relapsed platinum-resistant epithelial carcinoma of the ovary is a disease with a dismal prognosis. Bevacizumab and capecitabine have been used in carcinoma of ovary both as a single agent and with other chemotherapeutic medicine. A retrospective study has been performed to assess the efficacy of bevacizumab + capecitabine in relapsed platinum-resistant epithelial carcinoma of the ovary. Materials and Methods: Patients who suffered from relapsed platinum-resistant epithelial carcinoma of the ovary and received bevacizumab and capecitabine were included in the present study. The primary objective of this study was to assess response rate and progression-free survival (PFS). Treatment: Patients received capecitabine at a dose of 1250 mg/m2 twice daily from day 1 to day 14 in each cycle. Bevacizumab was given at a dose of 7.5 mg/kg on day 1 in each cycle. The cycle was repeated in every 3 weeks. Response evaluation was done using the Response Evaluation Criteria in Solid Tumor criteria and by Rustin criteria. Statistical Analysis: Statistical analysis was done using statistical software (SPSS 16, SPSS for Windows, SPSS Inc., Chicago, IL, USA). Results: We analyzed the data of 32 patients. The PFS was 10.51 (95% confidence interval [CI], 8.65–12.37) months. The overall survival (OS) was 20.53 (95% CI, 17.21–23.85) months. Four (12.5%) patients achieved complete response. Eighteen (56.25%) patients achieved partial response. The response rate was 68.75%. Four (12.5%) patients had progressive disease. Conclusion: Response rate, PFS, and OS of patients in this study are comparable to those of other published studies. Hence, bevacizumab + capecitabine can be used in relapsed platinum-resistant carcinoma of the ovary. The incidence and severity of bevacizumab-induced side effects are relatively lower in this study. Hence, bevacizumab can be given at a lower dose with comparable efficacy and tolerable side effects.

Editorial Expression of Concern: birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy

Editorial Expression of Concern: birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy

Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy

Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy

RETRACTED ARTICLE: Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy

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.

Abstract 212: Withaferin A in combination with cisplatin targets CD44 and Oct4 positive cancer stem cells in ovarian cancer

Abstract Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly, carboplatin coupled with paclitaxel. Although this treatment regimen is initially effective in a high percentage of cases, it is associated with severe side effects and within 6 to 24 months of initial treatment, tumor relapse occurs, which is attributed to the carcinomas having become platinum-resistant. Due to the poor survival of women with platinum-resistant carcinomas, and the severe side effects an alternative treatment strategy is warranted. We developed a novel strategy that combines cisplatin with withaferin A (WFA). WFA, a bioactive compound isolated from the plant Withania somnifera, is used in the US as an over-the-counter dietary supplement. More recently, it has been shown to prevent tumor growth, angiogenesis, and metastasis. In addition, WFA has been reported to inhibit Notch 1 signaling an important signaling pathway for the self-renewal and maintenance of cancer stem cell population. Based on this information, we hypothesize that a novel combination of withaferin A and cisplatin can target ovarian cancer cells and also ovarian cancer stem cells, which can reduce the cisplatin side effects and recurrence of ovarian cancer. Our hypothesis is supported by our preliminary studies in which epithelial ovarian cancer cell lines (A2780 and CaOV3 and A2780/CP70) when co-treated with low doses of the WFA (1.5 µM) and cisplatin (20 µM), resulted in inhibiting 80 to 90% cell proliferation within 48 h of treatment. In contrast, same concentration of each drug when used alone exhibited only 15% to 20% inhibition, respectively. In addition, treatment of nude mice bearing orthotopic ovarian tumors with WFA/cisplatin combination resulted in 80 to 90% reduction in tumor growth and complete inhibition of metastasis to other organs. In addition, treatment of mice bearing ovarian tumors with WFA/cisplatin combination showed a significant reduction in CD44 positive cancer stem cells analyzed by immuno-staining and western blot analysis of the CD44 protein. Tumors collected from mice treated with cisplatin alone revealed enrichment of CD44 positive cancer stem cells and expression of CD44 protein. Analysis of Notch1 signaling gene and its downstream signaling gene Hes1 showed a significant down regulation of expression. Notch1 plays an important role in renewal and maintenance of cancer stem cells which are reported to be chemo-resistance and play critical role in recurrence of cancer. Based on our results, we conclude that WFA/cisplatin combination therapy not only suppresses ovarian tumor growth but minimizes/eliminates cancer stem cell population, hence reduces the drug resistance and recurrence of cancer. This work was support by funds from James Graham Brown Cancer Center. Presenting author is a post-doctoral fellow. Citation Format: Sanjay K. Singh, J C. States, Sham S. Kakar. Withaferin A in combination with cisplatin targets CD44 and Oct4 positive cancer stem cells in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 212. doi:10.1158/1538-7445.AM2014-212

Development of a high-throughput screen for inhibitors of replication protein A and its role in nucleotide excision repair

The heterotrimeric protein, replication protein A (RPA), is essential for DNA repair and replication. RPA is a viable target in the treatment of cancer as many chemotherapeutic agents act by blocking DNA replication. Furthermore, inhibition of RPA could prove useful in treating cancers that have acquired resistance to DNA damaging agents through enhanced DNA repair mechanisms as has been observed with certain platinum-resistant carcinomas. In an effort to identify inhibitors of RPA, we employed a novel fluorescent reporter and established a homogeneous high-throughput screening assay to measure RPA's DNA binding activity. Using this assay, we have screened a collection of small molecules and determined the effect they have on the RPA-DNA interaction. Of the 2000 compounds screened, 79 scored positive for inhibition of RPA binding activity. Secondary screenings were performed using an electrophoretic mobility shift assay; of the 79 compounds, 9 scored positive and were further characterized in titration experiments to determine the most potent inhibitor, resulting in several compounds showing an IC50 in the low micromolar range. Fluorescence polarization analyses were also performed to determine the mechanism of inhibition for each compound. Validation of the inhibitory activity of selected compounds was verified using in vitro nucleotide excision repair (NER) catalyzed excision of a single cisplatin lesion in a duplex DNA. The identification and use of RPA inhibitors may aid in inhibiting NER activity that could potentially circumvent resistance to certain chemotherapeutic agents as well as be useful in the characterization of RPA and its interaction with DNA.

Gemcitabine salvage chemotherapy for patients with gynecologic malignancies of the ovary, fallopian tube, and peritoneum.

The efficacy and toxicity of gemcitabine salvage chemotherapy was evaluated in 27 heavily pretreated patients with recurrent and progressive ovarian, fallopian tube, or peritoneal cancer. At least one platinum-based chemotherapeutic regimen had failed in each patient. The median number of previous chemotherapy regimens and cycles of chemotherapy was 4 and 23, respectively. A total of 124 cycles of gemcitabine were delivered (median, 3 cycles). Hematologic toxicity included four patients with grade 3/4 thrombocytopenia and two patients with grade 3/4 neutropenia. Thrombocytopenia and neutropenia resulted in eight dose reductions and a single 1-week treatment delay. Nonhematologic side effects were well tolerated and largely self-limiting. No complete responses were observed. Three patients (11%) demonstrated partial responses to therapy. The duration of response was 7 months for two of the responders and 5 months for the third responder. Stable disease was observed in 14 patients (52%), in whom the median progression-free interval was 5 months. In conclusion, among heavily pretreated patients, gemcitabine has limited antitumor activity in platinum-resistant carcinomas of the ovary, fallopian tube, and peritoneum. The role of gemcitabine in the treatment of gynecologic malignancies of the ovary, fallopian tube, and peritoneum will be determined by studies that define the efficacy of multiagent regimens of chemotherapy that include gemcitabine and by studies that include patients who have been less heavily pretreated.