tumor cells. 0 The most promising mAb, muMAb4D5, was evaluated 3 M OUNT S INAI J OURNAL OF M EDICINE in a phase I study to assess safety, pharmacokinetics, and tumor localization. This mAb against HER was well tolerated and localized in tumors Ramelteon expressing HER protein, though patients did develop a HAMA response. MAb4D5 was humanized by Genentech 9 to minimize the emergence of a HAMA response, and was provided to academic laboratories for extensive preclinical characterization in tumor cell lines as a sin- gle agent and in combinations with Cyclophosphamide chemotherapeutic agents. The results from the preclinical studies sup- ported clinical evaluation of the humanized MAb4D5, now known as trastuzumab (Herceptin).

Successful clinical studies involving Genentech and academic investigators resulted in the FDA approval of Her- ceptin for patients with certain types of breast cancer in 998. Though the rationale for HER/neu as a target for cancer drug discovery occurred through research conducted in academic laboratories, Genentech was the industry driver developing a mAb that served as an important tool providing proof-of-concept data as well as insights into purchase Lacosamide how mAbs could be used in the clinic against HER. Through academic collaborations, Genentech was able to generate pre- clinical supportive data as well as the clinical stud- ies that resulted in Herceptin’s FDA approval. Though trastuzumab is effective in some HER- overexpressing breast cancer patients, the biomarker determination of HER and the underlying mecha- nism of action is an active area of study for both academia and industry.

This includes which method- ology (eg, immunohistochemistry versus fluorescent in situ hybridization) to use in determining HER sta- tus to select patients for treatment with trastuzumab. Trastuzumab is a chimeric humanized mouse anti- body currently approved for patients with certain types of breast cancer in specified single-agent and combination modalities and is marketed by Genen- tech/Roche. TARGETING BCR-ABL FOR THE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA The Philadelphia (Ph)  order Lacosamide chromosome is derived from a translocation involving regions of chromosomes 9 and , creating a fusion of the breakpoint cluster region (BCR) gene with the gene encoding the ABL, a SRC-related tyrosine kinase important in cellular proliferation and differentiation. The result- ing BCR-ABL fusion protein is constitutively acti- vated, leading to cellular transformation, and it is responsible for the development of most chronic 36 myelogenous leukemias (CML). 3 Small molecules targeting BCR-ABL have been clinically approved for the treatment of Ph + CML, and the discovery and development of these agents was enabled in large part by work conducted in concert by academic institutions and pharmaceutical companies.

High- throughput screening efforts at Novartis Pharmaceu- ticals led to the identification of a small-molecule ATP-competitive inhibitor of BCR-ABL, STI-57 (ima- tinib, Gleevec/Glivec), which was approved in 00 for Ph + CML. Imatinib is the first example of an anti- cancer agent that specifically targets a mutant protein expressed by tumor cells and responsible for aberrant cell proliferation. Because it specifically targets tumor cells, imatinib has achieved complete remissions in CML without significant toxicities. 4 Although most CML patients initially respond to imatinib, acquired resistance to this agent occurs in select patients through long-term use. Studies conducted at aca- demic institutions infants revealed the molecular mechanism for resistance, which ultimately enabled the discovery and development of next-generation therapeutics for imatinib-resistant CML. Dr Charles Sawyers at the Uni- versity of California, Los Angeles, first identified the point mutation within the kinase domain of BCR-ABL that conferred resistance to imatinib therapy, and subsequently a collaboration between Dr Sawyers and Dr John Kuriyan at University of California Berkeley led to the identification of 5 dis