BMS-345541 + Dasatinib Resensitizes Carboplatin-Resistant, Recurrent Ovarian Cancer Cells

Johns Hopkins medical researchers discovered through proteomic analysis that RELA and STAT5 are upregulated in carboplatin resistant ovarian cancer cells, according to a published study appearing in the June 18 edition of PLoS One. Moreover, the researchers also demonstrated that BMS-345541 (a NF-kappaB inhibitor) and dasatinib (a STAT5 inhibitor) could resensitize carboplatin-resistant, recurrent ovarian cancer cells.

Although most ovarian cancer patients are initially responsive to platinum-based chemotherapy, almost all develop recurrent chemoresistant tumors. For this reason, Johns Hopkins researchers set out to determine the scientific underpinnings of carboplatin drug resistance in ovarian cancer cells. The researchers compared the proteomes of paired primary and recurrent post-chemotherapy, high grade serous ovarian carcinomas from nine ovarian cancer patients.

As compared to the primary tumors, more than one-half of the recurrent tumors expressed higher levels of several proteins including:  CP, FN1, SYK, CD97, AIF1, WNK1, SERPINA3, APOD, URP2, STAT5B and RELA (NF-kappaB p65).  A short hairpin RNA (shRNA) is a sequence of RNA that makes a tight hairpin turn which can be used to silence gene expression through so-called “RNA interference.” Based on shRNA screening for the upregulated genes in in vitro carboplatin-resistant ovarian cancer cells, the researchers determined that simultaneous silencing of RELA and STAT5B was the most effective way to resensitize tumor cells for carboplatin treatment.

In an attempt to recreate the same results achieved with gene silencing through therapeutic drug use, the researchers used BMS-345541 (a NF-kappaB inhibitor) and dasatinib (Sprycel®)(a STAT5 inhibitor)  to significantly enhance cell sensitivity to carboplatin. The researchers also discovered that expression of RELA and STAT5B enhanced Bcl-xL promoter activity; however, treatment with BMS-345541 and dasatinib decreased such activity.

Accordingly, the researchers concluded that proteomic analysis identified RELA and STAT5 as two major proteins associated with carboplatin resistance in recurrent ovarian cancer tumors. Furthermore, the study results reveal that NF-kappaB and STAT5 inhibitors could resensitize carboplatin-resistant, recurrent ovarian cancer cells, thereby suggesting that these inhibitor drugs can be used to benefit select ovarian cancer patients.

Source: Jinawath N, Vasoontara C, Jinawath A, et. al.  Oncoproteomic analysis reveals co-upregulation of RELA and STAT5 in carboplatin resistant ovarian carcinoma. PLoS One. 2010 Jun 18;5(6):e11198.

2 thoughts on “BMS-345541 + Dasatinib Resensitizes Carboplatin-Resistant, Recurrent Ovarian Cancer Cells

  1. Dear, sir.
    My mother is suffering from CA OVARY stage 3C. She underwent 4 cycles of carboplatin based chemotherapy(however resistant) followed by a debulking operation. Post operatively good after 6 months she again presents with progressive ascites. We have given her 6 cycles of carboplatin plus gemcitabine combination, still the ascites seems to be non responsive. With about 5 litres of ascites being drained this month(after 6th cycles of combination chemo).
    Dear doctor can you please advise me the needful. Kindly save my mother.
    Thank you sir.

    N.Satya Prasad.
    ph no:+919989521171
    pg in orthopaedics

    Dated:08 JULY 2011

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    • Dear Dr. Prasad:

      Please forgive our inordinate delay in getting back to you. We are so sorry to hear about your mother. Please let her know that she is in our thoughts and prayers. We assume that your mom is resident in India given the “91” country code listed in the telephone number that you provided to us. First and foremost, you should be aware that Libby’s H*O*P*E* does not render medical advice and we are not medical doctors.

      We do have a few thoughts that you may want to take into account when speaking with your mother’s doctor(s). First, your mom’s doctor may want to consider the drug catumaxomab (trade name: Removab). Removab contains the trifunctional antibody, catumaxomab, which through its targeted mechanism of action destroys cells from EpCAM positive carcinomas. The antibody recognizes a protein on the surface of cancer cells, the so-called EpCAM molecule. It simultaneously recruits immune system cells, and activates them to destroy the cancer cells. Removab is used to treat malignant ascites in patients when standard treatment is not available or is no longer feasible. For the benefit of our readers, malignant ascites is an accumulation of fluid in the abdominal cavity (peritoneal cavity) resulting from certain types of cancer, such as ovarian carcinomas.

      Removab is only approved for clinical trial use in the U.S. However, the drug is European Union-approved for intraperitoneal use against malignant ascites. As of this writing, we could only locate four open clinical trials which are testing Removab. For a list of the open clinical trials involving Removab, click here. We could not locate any Removab clinical trials in India. Notably, Removab treatment of malignant ascites in patients with chemotherapy-refractory ovarian cancer was found effective in a phase 2 clinical trial, which was reported at the 2011 American Society of Clinical Oncology annual meeting.

      Another provocative study raises that hypothesis that bevacizumab (trade name: Avastin) may also be effective against malignant ascites. See “Intraperitoneal VEGF inhibition using bevacizumab: a potential approach for the symptomatic treatment of malignant ascites?” . Unfortunately, we could only find one announced (but not yet open) Indian clinical trial involving carboplatin, paclitaxel and bevacizumab (Avastin); however, it appears to involve primary treatment of ovarian cancer, as compared to recurrent ovarian cancer. Our search for general ovarian cancer clinical trials in India produced only six studies, which are either not open for new patients or seem inappropriate given your mom’s case.

      Our search of Indian solid tumor clinical trials identified 12 open studies. The only study that may be relevant with respect to your mom’s treatment is the E7389 (eribulin mesylate) + carboplatin phase I study. We did identify a 2009 phase II study of E7389 (as a monotherapy) in platinum resistant ovarian cancer. Unfortunately, the response rate was only 6% when the drug was used as a monotherapy.

      Is there another country location where your mom can be treated? Obviously, this concept will depend on whether she is able to travel at this point. If travel is possible, please let us know and we will perform broader ovarian cancer clinical trial searches for you and your mother.

      We hope that the limited information above is helpful. As always, if you have additional questions, please don’t hesitate to contact us through the “Contact” tab located on the website homepage.

      Best regards,

      Paul

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