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Resumo de Biologia Celular sobre Proteossomos....

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Phase II clinical experience with the proteasome inhibitor bortezomib (formerly PS-341) in patients with indolent lymphomas Abstract No: 2277 Citation: Proc Am Soc Clin Oncol 22: page 566, 2003 (abstr 2277) Author(s): O. A. O'Connor, J. Wright, C. Moskowitz, B. Macgregor-Cortelli, D. Straus, D. Horse-Grant, D. Schenkein, A. Zelenetz; Memorial Sloan-Kettering Cancer Center, New York, NY; National Cancer Institute, Bethesda, MD; Millenium Pharmaceuticals, Cambridge, MA Abstract: The ubiquitin proteasome pathway plays an essential role in the degradation of most intracellular proteins in eukaryotic cells. The 26S proteasome, a multicatalytic protease, degrades regulatory proteins invovled in cell cycle control. Some targets of ubiquitin proteasome mediated degradation include p53, p21, NF-κB, IκB and bcl-2. Preclinical data have confirmed that inhibitors of the proteasome act through multiple mechanisms to arrest tumor growth. Phase I trials have confirmed tolerability of the drug. Correlative studies performed in the Phase I and II clinical trials have established a dose response relationship between dose and the extent of proteasome inhibition in peripheral blood mononuclear cells. To date, we have administered over 33 cycles of PS-341 (average 2.4 per patient) to 14 previously treated patients with relapsed or refractory indolent lymphomas (small lymphocytic lymphoma, SLL (n=2); follicular lymphoma, FL (n=7) and mantle cell lymphoma, MCL (n=5)). All patients signed an informed consent and had to have adequate hepatic and renal function. Adequate hematologic counts including an ANC of > 1000 cells/μl and a platelet count > 100,000/μl were also required. All patients had received some form of treatment prior to receiving PS-341, including: CHOP; CVP; CTX/fludarabine; and/or rituximab. Patients were treated at a dose of 1.5 mg/m2 twice weekly for 2 consecutive weeks with a 1 week rest period. Some patients experienced a mild thrombocytopenia that resolved during the rest week. Two patients developed peripheral neuropathies (one sensory, one motor). Restaging studies were performed after two complete cycles of therapy. Both patients with SLL were found to have stable disease after 2 and 4 cycles respectively. Of the evaluable patients with FL, there was one CR, three PR and 2 with stable disease. Major responses were also seen in 3 patients with MCL, all three of whom achieved a PR after only 2 cycles of treatment, with 1 patient having over an 80% reduction in tumor volume. These preliminary data support the biological activity of PS-341 in patients with low-grade lymphomas. Accrual to this trial continues.

Phase I trial of 17-AAG (17-allylamino-17-demethoxygeldanamycin) in patients (pts) with advanced cancer. Abstract No:

795

Citation:

Proc Am Soc Clin Oncol 22: page 198, 2003 (abstr 795)

Author(s):

D. B. Solit, M. Anana, G. Valentin, A. De La Cruz, W. Tong, K. Busam, V. Reuter, W. K. Kelly, N. Rosen, H. Scher; Memorial Sloan-Kettering Cancer Center, New York, NY

Abstract:

17-AAG is an ansamycin antibiotic that binds to a highly conserved pocket in the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of a subset of signaling proteins. Treatment with 17-AAG causes the proteasomal degradation of Hsp90 client proteins, which include HER2, steroid receptors, Raf and Akt. We initiated a phase I study of 17-AAG to define the MTD, toxicity profile, and pharmacodynamics of this agent in pts with advanced malignancies. Pts were treated with doses ranging between 5 and 157 mg/m2 using one of three treatment schedules: days 1-5 of a 21d cycle (5-80 mg/m2), days 1-3 of a 14d cycle (80-112 mg/m2) and most recently days 1, 4, 8, and 11 of a 21d cycle (112-157 mg/m2). To date we have enrolled 40 pts (median age 56: range 22-78) with prostate cancer (ca) (13 pts), breast ca (8), renal ca (5), lung ca (4), bladder ca (3), melanoma (3), CML (1) and others (3). Pts have received a median of 2 cycles (range: 112). Toxicity, in particular hepatic, was schedule dependent. Dose limiting toxicities (reversible hepatitis and diarrhea) were reached with the daily x 5 and daily x 3 schedules. No grade 3/4 toxicities have been observed with the twice-weekly schedule and dose escalation continues. Pharmacokinetic data for the 157 mg/m 2 dose level showed a t1/2 of 3.8hrs with peak levels of 7.18μM for 17-AAG; and t1/2 of 9.6hrs with peak levels of 1.34μM for the active metabolite 17-AG. These concentrations exceed those associated with decreases in target protein expression in vitro and in xenograft models. No objective responses have been seen, although 9 of 34 evaluable pts had stable disease beyond 3 months. Correlative studies include collection of peripheral blood lymphocytes and pre/post treatment skin biopsies to study therapy induced changes in Hsp90 client proteins and proliferative index respectively. Tumor biopsies have been

collected in selected pts. At the meeting updated enrollment, response and correlative data will be reported. Supported by R21 85506, CA05826, CaPCURE....