Cancer Therapeutics(1) Taxane-monoclonal antibody conjugates. Current cancer chemotherapy is based on the premise that rapidly proliferating tumor cells are more likely to be killed by cytotoxic drugs. Unfortunately, the difference in activity of current drugs against tumor tissues in comparison to healthy tissues is relatively small. The amount of a drug required to achieve clinically effective level of cell kill often causes severe damage of actively propagating non-malignant cells such as cells of the gastrointestinal tract and bone marrow, resulting in a variety of undesirable side effects. Therefore, it is very important to develop new chemotherapeutic agents with improved tumor specificity.
The discovery of antigens that are particularly over-expressed on the surface of cancer cells suggests that by using certain antibodies to selectively "mark" tumor cells, malignant tissues could be distinguished from normal tissues. Monoclonal antibodies (mAbs), which have shown high binding specificity for tumor-specific antigens, could fulfill this task. In fact, these mAbs could be used as vehicles to deliver cytotoxic drugs selectively to tumor cells. A drug-mAb conjugate would target the tumor cells by binding to the antigens on their surfaces. The conjugate is then internalized and releases the original cytotoxic agent in its active form.
The practical efficacy of such immunoconjugates heavily depends on the nature of the cytotoxic agents as well as the tumor specificity of mAbs. Paclitaxel (TAXOL®) and docetaxel have brought about significant impact on the current cancer chemotherapy, mainly because of their unique mechanism of action but seriously suffer from the lack of tumor specificity and multi-drug resistance (MDR). Thus, it is beneficial to develop immunoconjugates of these drugs. However, it is obvious from the current understanding of the requirements for effective immunoconjugates that the cytotoxicity level ofpaclitaxel or docetaxel is not sufficient as the cytotoxic component of the conjugate for human clinical use. In addition, those conjugates are anticipated to be inactive against tumors expressing MDR.
On the basis of the structure-activity relationship (SAR) study of taxoids accumulated in Dr. Ojima's laboratory at Stony Brook in collaboration with Dr. Bernacki's laboratory at Roswell Park Cancer Institute in Buffalo, he has developed a series of highly potent second-generation taxoids. Most of these taxoids exhibited 2-3 orders of magnitude higher potency than those of paclitaxel and docetaxel against drug- resistant cell lines expressing MDR phenotypes. Accordingly, Dr. Ojima can develop novel chemotherapeutic agents with high potency and exceptional tumor specificity by linking these second-generation taxoids with mAbs. He and his collaborators have already obtained highly promising preliminary results against A-431 human squamous cancer xenographs in SCID mice, targetting EGFR as the tumor specific antigen. Thus, this basic biomedical technology has been proven to be highly effective.
ICB&DD is now in the position to explore and identify new and specific antigens on each cancer type, prepare specific monoclonal antibodies, and conjugate them with extremely potent taxane anticancer agents. This will be achieved through collaborations of immunologists, medicinal chemists, pharmacologists, cell biologists, and computational biologists at Stony Brook as well as pharmaceutical firms in New York State and elsewhere.
(2) Signaling enzyme inhibitors. Signal transduction pathways control eucaryotic cell growth, differentiation, and survival by directing extracellular signals into the cell interior. In recent years, a great deal of progress has been made in identifying the protein components of eucaryotic signaling pathways. This effort has been driven in large part by the realization that the signaling mechanisms that control cell proliferation are associated with tumor malignancy. The design of signal transduction inhibitors is therefore an important strategy for developing anticancer therapeutics. For example, tyrosine kinases play a key role in normal cell growth, but inappropriate activation of tyrosine kinase signaling (by mutation, overexpression, or chromosomal rearrangement) often occurs in human cancers. In May 2001, the FDA approved the first small-molecule tyrosine kinase inhibitor, STI-571 (Gleevec) from Novartis, which has proven to be an effective therapy for chronic myelogenous leukemia. Signal transduction is the focus of approximately 25 laboratories at SUNY Stony Brook. Many of these laboratories study unique molecular targets with defined enzymatic activities. The members of Institute are the leaders among these laboratories. For example, Dr. R. Johnson studies adenylyl cyclase; Dr. Miller studies tyrosine kinases such as Abl and insulin-like growth factor I receptor; Dr. Malbon (Advisory Board Member) studies G-protein coupled receptors and their effectors; Dr. Haltiwanger studies enzymes that catalyze protein glycosylation. Furthermore, studies in many laboratories at Stony Brook have led to the identification of new signaling enzymes that would represent targets for drug design.
Accordingly, this integrated collaborative project of ICB&DD on the novel signaling enzyme inhibitors with medicinal chemists will find a potential "Gold Mine" for discovery of new mechanism-based anticancer agents, which has high specificity to tumors, hence minimize undesirable side effects to cancer patients.
Another important and related area in cancer research at the Institute is in the development of agents that could interfere with protein-protein interactions in signal transduction pathways. For example, Dr. Raleigh studies the multidomain adaptor protein c-Crk. This protein plays a key role in orchestrating signaling pathways leading to proliferation, differentiation, cell adhesion, and cytoskeletal reorganization. Dafna Bar-Sagi (Project Member) studies the interactions between the guanine nucleotide exchange factor Sos and its molecular targets. In these cases, specific inter- and intradomain interactions can be exploited to design molecules that block function. With close collaboration with medicinal chemists and Chemical Synthesis/Combinatorial Chemistry Laboratory of the Institute, drug-design synthesis, SAR studies will efficiently be performed, which would lead to drug discovery of novel anticancer agents.
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