Senescence, an underappreciated cell dormancy phenotype that occurs upon treatment with many cytotoxic drugs, represents a new paradigm in drug development. This phenotype imparts detrimental effects on the local tumor microenvironment, primarily due to pro-inflammatory properties that drive resistance and metastatic progression. Thus, there is an unmet need to screen novel anti-cancer drugs for their senescence inducing potential. Another mode of chemotherapy-related dormancy that also needs to be modeled in modern drug development is the enrichment of tumor initiating cells with successive rounds of treatment. Collectively, both forms of tumor dormancy equate to poor clinical response that necessitates second- and third-line treatment leading to irreversible toxicities that negatively impact quality of life and eventually render patients ineligible for continued treatment. Thus, the design and evaluation of potent, metabolically stable, novel anti-cancer drugs selected to circumvent senescence will have high impact for the treatment of recalcitrant cancers in the first- line and metastatic setting. This project will evolve our previos studies with a microtubule inhibitor, discodermolide, to synthesize a series of novel analogues that have modifications of the lactone ring and diene moieties that we hypothesize influence tumor cell kill and senescence induction in cells. The overall goal of this program is to select lead compounds that have: (A) a low propensity to induce senescence, (B) high induction of tumor cell death in chemorefractory cell types, such as tumor initiating cells, and (C) minimal toxicity, as determined from measures of cardiopulmonary function and histology, nerve conduction, and neuropsychology. These studies will be applied to cell-based and whole-animal models of recalcitrant tumor types, namely triple negative breast cancer, non-small cell lung cancer and serous ovarian cancer. Finally, in-depth testing of two lead candidates in mouse models of patient-derived cancer will enable selection of a highly efficacious novel anti-tumor agent suitable for first in-human testing. This project brings together a diverse team of experts committed to evolving the rational design and synthesis of novel microtubule targeting drugs to alleviate the suffering and mortality of cancer patients.
Therapeutically recalcitrant tumors are treated with a cocktail of chemotherapy drugs, including Taxol; however many patients do not respond and suffer toxic side effects, some of which are long-lasting and prevent them from receiving future therapy. This problem has encouraged scientists to search for and synthesize novel cancer chemotherapeutic drugs. This project seeks to develop novel anti-tumor drugs selected for minimal toxicity and maximal anti-tumor efficacy.
| Yang, Chia-Ping Huang; Wang, Changwei; Ojima, Iwao et al. (2018) Taxol Analogues Exhibit Differential Effects on Photoaffinity Labeling of ?-Tubulin and the Multidrug Resistance Associated P-Glycoprotein. J Nat Prod 81:600-606 |
| Mathew, Deepti; Wang, Yanhua; Van Arsdale, Anne et al. (2018) Expression of ?V-Tubulin in Secretory Cells of the Fallopian Tube Epithelium Marks Cellular Atypia. Int J Gynecol Cancer 28:363-370 |
| Nadaradjane, Celine; Yang, Chia-Ping Huang; Rodriguez-Gabin, Alicia et al. (2018) Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners. J Nat Prod 81:607-615 |
| Samaraweera, Leleesha; Adomako, Alfred; Rodriguez-Gabin, Alicia et al. (2017) A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC. Sci Rep 7:1900 |
| Prota, Andrea E; Bargsten, Katja; Redondo-Horcajo, Mariano et al. (2017) Structural Basis of Microtubule Stabilization by Discodermolide. Chembiochem 18:905-909 |
| Yang, Chia-Ping Huang; Horwitz, Susan Band (2017) Taxol®: The First Microtubule Stabilizing Agent. Int J Mol Sci 18: |
| Yang, Chia-Ping Huang; Yap, Eng-Hui; Xiao, Hui et al. (2016) 2-(m-Azidobenzoyl)taxol binds differentially to distinct ?-tubulin isotypes. Proc Natl Acad Sci U S A 113:11294-11299 |
| Frimer, Marina; Levano, Kelly S; Rodriguez-Gabin, Alicia et al. (2016) Germline mutations of the DNA repair pathways in uterine serous carcinoma. Gynecol Oncol 141:101-7 |
| Andreopoulou, Eleni; Schweber, Sarah J; Sparano, Joseph A et al. (2015) Therapies for triple negative breast cancer. Expert Opin Pharmacother 16:983-98 |
| Wani, Mansukh C; Horwitz, Susan Band (2014) Nature as a remarkable chemist: a personal story of the discovery and development of Taxol. Anticancer Drugs 25:482-7 |
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