(3)難治性卵巣がんに対する新たな分子標的治療の開発を目指した基礎的研究 : 基礎から臨床へ(<特集>第61回学術講演会シンポジウム3「卵巣癌の新たな治療戦略-基礎から,そして臨床から-」)

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New molecular targeting therapy for intractable ovarian cancer: from basic to clinical studies Clear cell adenocarcinoma is an intractable type of surface epithelial ovarian cancer that is resistant to standard anticancer drugs. Both stage Ic and III clear cell adenocarcinoma have a poor prognosis. It was reported that multivariate analysis showed that only staging laparotomy was an independent indicator of better PFS in pTI cancer patients and that chemotherapy was not useful for improvement of PFS. This suggests that it is necessary to develop new molecular targeting therapy for clear cell adenocarcinoma. Drugs that treat cancer by targeting molecular changes specific to tumor cells are referred to as molecular targeting drugs and are expected to be superior to conventional chemotherapy for malignant tumors in terms of both selectivity and safety. Molecular targeting drugs are usually divided into antibodies and low molecular weight drugs, and are expected to contribute to the establishment of individually tailored therapy. We have carried out basic studies aimed at the development of new molecular targeting therapy for ovarian clear cell adenocarcinoma, since this is a refractory type of ovarian cancer. Antibodies: We created two human monoclonal antibodies (HMOCC-1 and HMOCC-2) directed against clear cell adenocarcinoma by using human monoclonal antibody-producing KM mice that were generated through the introduction of full-length human antibody genes into mice using the latest reproductive technologies. The antigen that we employed was expressed by RMG-I cells, a human clear cell adenocarcinoma cell line. It was found that HMOCC-1 showed positive immunohistochemical staining of the tumor in 90% of clear cell adenocarcinoma patients. It was a membrane glycoprotein and β3-G1cNAc-transferase-7, which is assumed to be one of the glucose transfer enzymes involved in tumor cell invasion, was required for antigen presentation. It was also found that HMOCC-1 prevented cells from binding to human peritoneal mesothelial cells. These findings suggest that HMOCC-1 may be clinically useful for molecular targeting therapy. In the case of HMOCC-2, it was found that positive immunohistochemical staining occurred in the tumors of 75.6% of clear cell adenocarcinoma patients. Its antigen was a membrane glycoprotein and it was the first human monoclonal antibody that recognized CA125-associated molecules, like OC-125 antibody. HMOCC-2 exhibited an antitumor effect on heterotransplanted RMG-I tumors, so HMOCC-2 was also expected to be clinically useful for molecular targeting therapy. Low molecular weight drugs: The transcription factor POU6F1 was shown to play an important role in the signaling pathway involved in the growth of clear cell glands via the lipid mediator LPA. This suggests the possibility that LPA or POU6F1 could be new molecular targets for the treatment of clear cell adenocarcinoma. A new synthetic retinoid (TAC-101) is suitable for oral administration, stable in the blood, and has a long duration of action. Due to these features, it is increasingly gaining attention. TAC-101 induced the apoptosis of surface epithelial ovarian cancer cell lines, especially for clear cell adenocarcinoma cell lines, and inhibited the growth of heterotransplanted RMG-1 tumors as potently as CDDP and PTX. When it was used with CDDP, the antitumor effect against clear cell adenocarcinoma cell lines was increased. In the present study, we succeeded in establishing new molecular targeting therapies that can inhibit the growth and invasion of ovarian clear cell adenocarcinoma. Further basic studies on various combinations of these new molecular targeting therapies might lead to the development of new regimens that have a potent antitumor effect and can contribute to prolonging survival by showing activity against clear cell adenocarcinoma, which is an intractable ovarian cancer.
2009-11-01

(3)難治性卵巣がんに対する新たな分子標的治療の開発を目指した基礎的研究 : 基礎から臨床へ(<特集>第61回学術講演会シンポジウム3「卵巣癌の新たな治療戦略-基礎から,そして臨床から-」)

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