New therapeutic options for chemotherapy-resistant metastatic breast cancer: the epot

[Rich66]

Drugs. 2008;68(2):139-46.Links

New therapeutic options for chemotherapy-resistant metastatic breast cancer: the epothilones.

Pronzato P.
Oncologia Medica, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy. pproza@tin.it
When taxanes were introduced as anticancer agents some 20 years ago, their broad spectrum of activity was striking and engendered renewed hope for cancer patients. However, they were not without their problems, including a susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein. The epothilones are a new class of chemotherapeutic agents that have a mechanism of action similar enough to the taxanes to retain their broad spectrum of activity, but different enough to escape the multidrug resistance caused by P-glycoprotein. These properties are especially promising for patients with metastatic breast cancer who have run out of therapeutic options as a result of multidrug resistance. Ixabepilone, a semi-synthetic analogue of epothilone B, has recently been granted US FDA approval for the treatment of chemotherapy-resistant advanced breast cancer. Approval was based on results from a phase III study of ixabepilone in combination with capecitabine, as well as phase II studies of ixabepilone monotherapy. Significantly prolonged progression-free survival and increased objective response rates were demonstrated in the phase III study when ixabepilone was administered in combination with capecitabine compared with capecitabine alone. The phase II trials demonstrated robust antitumour activity with single-agent ixabepilone in women with metastatic breast cancer that was resistant to taxanes, anthracyclines and capecitabine. Early data from phase I trials of KOS-1584 and sagopilone are positive and suggest that these drugs may also develop into useful chemotherapeutic agents. Significant, but manageable, toxicities have been observed with the epothilones. In particular, neuropathy has led to the uneven and slower than expected clinical development of ixabepilone as optimal administration regimens were established. Some differences in tolerability profiles exist between the different analogues. Overall, it is expected that the epothilones will play an important role in the treatment of breast cancer and other tumour types.

[Lori R]

Rich,
Thank you for continuing to keep us apprised of these new developments.

My daughter is a sophmore is highschool. Intially, my goal was to see her graduate. Now I am planning on being there to help her enroll in college, next goal is to see her graduate from college.

Your articiles continue to inspire hope that I can just keep on movin out that timeline.

Thank you so much....Lori

[Rich66]

1: Semin Oncol. 2008 Apr;35(2 Suppl 2):S22-30; quiz S40. Links

Clinical studies with epothilones for the treatment of metastatic breast cancer.

Vahdat LT.
Division of Hematology/Oncology, Weill Medical College of Cornell University, New York, NY 20021. ltv2001@med.cornell.edu
Standard cytotoxic chemotherapy of locally advanced or metastatic breast cancer includes the microtubule-stabilizing taxanes, but like other cytotoxic drugs their effectiveness is compromised by resistance that is either inherent or develops during treatment. Epothilones, which also stabilize microtubules but by a different mechanism, are in clinical development primarily to overcome taxane or multidrug resistance, based on potent preclinical antitumor activity against resistant tumor lines. Ixabepilone is the best-studied epothilone clinically and is active in patients with metastatic breast cancer that has been pretreated with, or had established resistance to, taxanes and/or anthracyclines. In a phase III trial in patients with anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer, adding ixabepilone to capecitabine significantly improved progression-free survival and the overall response rate compared with capecitabine alone. The primary toxicities associated with ixabepilone treatment are neuropathy and neutropenia, but both are generally manageable. Other epothilones currently in clinical studies are KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584, which have all shown activity in patients with pretreated or resistant metastatic breast cancer.

[Rich66]

A good overview of mbc approaches ending with a focus on epithilones:

http://www.oncolink.org/resources/ar...&ss=224&id=967