Toxicity problems continue to slow the development of CDK inhibitors

Breast cancer is one of the most prevalent tumor types, with a little over 200,000 cases expected to be diagnosed in the this year. Mortality rates declined by 2.3% between 1990 and 2000 due to improvements in diagnosis and treatment and 5-year survival rates now stand at 97% for localized tumors, 79% for tumors that have spread regionally and 23% for women with distant metastatic progression.

Treatment of breast cancer currently involves the use of hormonal and cytotoxic therapies. Tamoxifen remains the mainstay of the antihormonals class, with aromatase inhibitors such as atamestane and Eli Lilly's Evista (raloxifene) both vying to replace tamoxifen (for an expert analysis of hormonal therapies Click here ). Of the five major ATC-defined cytotoxic classes, vinca alkaloids, which include the taxanes, represent the largest in terms of sales. BMS’s Taxol (paclitaxel) once dominated not only the class but also the cytotoxic market as a whole. However, because of its patent expiry, it has lost its leading position to its rival, Aventis’ Taxotere (docetaxel; for an expert analysis of cytotoxic therapies click here). Taxotere is currently approved in the to treat patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. Last week it was announced that the FDA had approved the use of Taxotere in combination with doxorubicin and cyclophosphamide for the adjuvant (post surgery) treatment of patients with operable, node-positive breast cancer.

Innovative targeted therapies currently dominate the breast cancer pipeline, accounting for 70% of drugs in development for this indication (click here for a detailed analysis of breast cancer therapeutics). Cytotoxics are likely to remain the gold-standard therapy until at least 2008, when key patent expiries will occur. By this time several novel agents will have been commercialized.

Aberrations in cell cycle progression occur in the majority of human malignancies. The main pathway affected is the retinoblastoma (Rb) pathway. The tumor suppressor gene Rb is an important component in the G(1)/S transition and its function is abnormal in most human neoplas. Loss of Rb function occurs by the hyperactivation of the cyclin-dependent kinases (CDKs). Therefore, modulation of CDKs represents the target of a number of novel therapeutic agents currently in development. Efforts to obtain all-molecule CDK modulators yielded two classes of modulators: direct and indirect modulators. Direct CDK modulators are all molecules that specifically target the ATP binding site of CDKs. Examples for this group include flavopiridol.

Aventis' flavopiridol, a flavonoid derived from an indigenous plant from , has demonstrated potent and specific in vitro inhibition of CDKs in vitro, with IC50 values ranging from 3–300 nM. Flavopiridol produces a clear block in cell cycle progression at the G1/S and G2/M boundaries and moreover, preclinical studies demonstrated the capacity of flavopiridol to induce programmed cell death, promote differentiation, inhibit angiogenic processes and modulate transcriptional events. Early clinical studies have shown that it is possible to administer flavopiridol at a dose sufficient to produce plaa concentrations sufficiently high to inhibit CDK activity.

In this month's edition of the journal, Clinical Cancer Research, Tan et al have published results of a toxicity and pharmacokinetic study of metastatic breast cancer patients treated with a combination of Taxotere and flavopiridol. The initial study protocol in which Taxotere was administered at an initial dose of 60 mg/m(2) followed 24 hours later by a 72-hour infusion of flavopiridol at 50 mg/m(2)/d every 3 week was subsequently modified to a protocol in which the dose of Taxotere was reduced to 50 mg/m(2) and that of flavopiridol was modified to an escalating dose starting at 26 mg/m(2)/d administered as a 1-hour infusion daily for 3 days.

The combination of Taxotere and flavopiridol was seen to be biologically active, reducing phospho-Rb and increasing p53 nuclear staining. Clinical efficacy was also observed with the initial protocol producing 2 stable responses lasting >3 months in 5 women. The subsequent protocol was less effective producing only 1 partial response in 6 women. Unfortunately both protocols also produced serious dose limiting toxicity; grade 4 neutropenia (which accompanied grade 3 hypotension) in the initial protocol and grade 3 hypotension in the subsequent protocol.

The data from this study suggest therefore that despite evidence of clinical efficacy the use of flavopiridol with metastatic breast cancer will have to be further developed to limit associated toxicity. Whether this will be possible remains to be seen. The authors of the study suggest that the dose-limiting toxicities resulted from the combination of the two agents rather than from flavopiridol alone, however previous clinical data from trials in other cancers have show shown that flavopiridol is a poor monotherapy and success will more likely come through the use of combination approaches. The efficacy of flavopiridol when used in combination with other chemotherapeutics is due to sequence-dependent cytotoxic synergy. These effects are most marked when chemotherapy precedes flavopiridol and hence further studies will be necessary in order to optimize the dosing schedule and to see whether this can lower toxicity to manageable levels. One protocol currently being investigated involves the weekly administration of Taxotere followed 4 hours later with a 1 hour infusion of flavopiridol.

Source: Phase I Trial of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination with Docetaxel in Patients with Metastatic Breast Cancer. Clin Cancer Res. 2004 Aug 1;10(15):5038-5047.

This article is highlighted in the August 27th edition of DailyUpdates - Oncology, LeadDiscovery’s unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today’s bulletin click here