The majority of adults with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) eventually relapse, and those with relapsed disease have a high likelihood of treatment failure with currently available agents. New drugs that more effectively treat these diseases are needed. This proposal describes two exciting phase I clinical trials in the targeting of aberrant signaling and survival pathways in leukemic cells. The first trial investigates a novel, pharmacokinetically driven schedule of flavopiridol in ALL or AML. Given new laboratory data demonstrating critical differences between drug-protein binding in fetal bovine serum (FBS) vs. human plasma, early negative clinical studies with flavopiridol based on in vitro studies in FBS may have failed to reach (or maintain) drug levels necessary for in vivo clinical activity. Pharmacokinetic modeling based on in vitro studies in acute leukemia cells cultured in human plasma suggested that administering flavopiridol by 30 minute intravenous (IV) bolus followed by 4 hour continuous IV infusion (CM) would achieve an in vivo plasma drug concentration similar to that necessary to induce apoptosis in vitro. Preliminary results of an ongoing phase I clinical study using this dosing strategy administered weekly in patients with refractory chronic lymphocytic leukemia (CLL) demonstrated impressive clinical responses. In addition, acute tumor lysis was observed as a dose limiting toxicity. The proposed trial administers flavopiridol in the manner described for three consecutive days every three weeks based on in vitro and animal studies.
It aims to generate preliminary pharmacokinetic and phamacodynamic data to facilitate additional efficacy studies in ALL and AML. Investigations will then proceed to phase II trials and additional phase I trials in combination with other agents. The second trial in this proposal is a phase I combination study of the heat shock protein 90 (HspQO) inhibitor 17-allyamino-demethyoxygeldanamycin (17-AAG) with the proteasome inhibitor PS-341 (bortezomib, Velcade) in relapsed and refractory AML. Both agents act by altering normal cellular regulatory functions, 17-AAG by affecting chaperone function of Hsp90 and PS-341 by inhibiting the 20S proteasome. Due to inhibition of Hsp90 by 17-AAG, multiple client proteins including those important in survival pathways such as Akt are degraded. Inhibition of the 20S proteasome by PS-341 also has multiple effects, mainly due to loss of NF-KB activation (resulting from the inhibited proteasome's failure to degrade the NF-kB inhibitor IkB). Individually, both agents have been shown to have anti-leukemia efficacy. Treatment of leukemic cells with PS-341 results in a stress-response which includes upregulation of Hsp90 leading to resistance to apoptosis, and we hypothesize that treatment of AML patients with both 17- AAG and PS-341 will be an effective method to overcome treatment resistance. If the regimen is well tolerated, a phase II study will be performed, including patients with high risk, untreated AML. Both studies described above will serve as the foundation for the career development of Dr. William Blum, a promising young clinical investigator in the area of experimental therapeutics for ALL and AML. The mentors for the candidate's career development are Dr. Clara Bloomfield, Dr. John Byrd, and Dr. Guido Marcucci at The Ohio State University. They will be assisted in laboratory mentoring by Dr. Denis Guttridge and Dr. James Dalton. ? ? ?
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