Research Grants Awarded
A Phase-II Pre-Clinical Study of Paclitaxel-Monoclonal Antibody Conjugates for Targeted Chemotherapy of Breast Cancer
Background: 1. Chemotherapy is a major strategy in breast cancer treatments. 2. Taxanes (paclitaxel, PTX) are an important class of anticancer drugs used against breast cancer. 3. Taxanes suffer from dose-limiting toxicities. 4. The insolubility of taxanes necessitates the use of allergenic excipients to clinical formulations. 5. Targeted therapy is a new approach to cancer treatment, where a tumor-recognizing molecule (a monoclonal antibody, MAb) acts as a vehicle for tumor-specific delivery of cytotoxic agents, leading to high therapeutic indices and low systemic toxicities. Objective/Hypothesis: The advantage of targeted drug delivery has been demonstrated in a phase-I, proof-of-principle study. The objective of this proposal is to apply the phase-I results to produce water-soluble, breast cancer-specific PTX-MAb conjugates and study their antitumor behavior in a breast-tumored mouse model. The ultimate goal of this research is the development of breast cancer-targeting chemotherapeutic agents for clinical application. Specific Aims (SAs): 1. To synthesize water-soluble conjugates of PTX to the anti-EGFR MAB, C225 (Erbitux?¥). 2. To identify, as candidates for therapy students, congeners with the highest drug load, antigen-binding ability and cytotoxicity. 3. To evaluate the therapeutic efficacy and toxicity of the conjugates identified in SA2 in a mouse model of human breast cancer. Study Design: The synthetic technology for the production of taxane-MAb conjugates has been developed (see Preliminary Data). This technology will be used here to synthesize PTXC225 conjugates with improved therapeutic features (SA1). Using MDA-MB-468 human breast cancer cells, the synthesized conjugates will be tested for cell-binding and cytotoxic activity, to select congeners with the highest potency (SA2). Selected conjugates of SA2 will be used in therapy and toxicity studies in a MDA-MB-468 mouse model (SA3). Potential Outcomes/Benefits: It has been shown that: 1. Synthesis of PTX-MAb conjugates is chemically feasible. 2. Conjugates have higher cytotoxicity and apoptosis induction that the free drug. Armed with this information, high-drug-load, high potency breast tumor-targeting water-soluble conjugates will be prepared and protocols for their applications as targeting anti-breast tumor drugs will be developed. Accomplishment of the following is expected: 1. Tumor-specific delivery of taxol to primary and micrometastatic tumors. 2. Reduction of the drug toxicity and side effects due to the pro-drug nature of the conjugated PTX and tumor-specific drug delivery. The pro-drug is inactive and non-toxic. 3. Elimination of allergenic solubilizers used in the current clinical formulations of taxol. 4. High near-term clinical translation potential due to the present clinical use of both PTX and C225.
Chemotherapy is a powerful weapon in the fight against breast cancer and the role of this treatment method in the improvement of the quality of life and survival rates of breast cancer patients can not be overemphasized. However, obstacles, such as drug resistance and toxicity, leave the field open to a need for improvements in the currently available treatment strategies. Tumor-targeted therapy of cancer began mainly by the development of monoclonal antibodies. These are proteins produced by the immune system in response to intrusions by bacteria, viruses, and cancer cells. The name "monoclonal antibody" refers to structurally unique antibodies, which have the ability to recognize and attach to cancer tumors. They are, therefore, useful as vehicles for targeted delivery of anti-cancer drugs to cancer tumors. In this application, we propose to employ the tumor-recognizing ability of monoclonal antibodies in a "guided missile" approach, to target breast cancer tumors and deliver taxol, an important antitumor drug with proven activities against this disease. Thus, the anti-breast cancer antibody, Herceptin, will be chemically attached to taxol to produce a tumor-recognizing and tumor targeting construct (referred to here as the "drug conjugate"). Once in the body, the antibody component (the guiding system) of the drug conjugate will find, and localize in, the breast cancer tumors. At this stage, and as a result of a pre-designed chemical structure, the drug component (the warhead) will be released to destroy the tumor. Since the conjugate will be administered to the whole body by injection, it will have the potential of also killing the hidden (or the metastasized) tumors. In a phase-I study, we demonstrated the advantage of the antibody targeting approach over the use of free, "unguided" taxol in controlled experiments. Here, we propose to use those results to refine the structural design of the drug conjugates and conduct animal studies to develop protocols to treat breast cancer by a tumor-targeting drug. Based on our preliminary results, and the available scientific literature, the research proposed here is expected to lead to the following gains: 1. Tumor-specific delivery of the drug (taxol) to primary, and small, hidden (metastasized) tumors. 2. Reduction of the administered doses of the drug due to this tumor-specific drug delivery, and thereby, lowering drug toxicity and side effects. 3. Elimination of toxic additives used in the current clinical formulations of taxol as a result of the water solubility of the proposed conjugates. 4. High near-term potential for the clinical use of these drug conjugates due to the present clinical use of both taxol and the antibody Herceptin