Chemical Biology and Molecular Medicine

The Chemical Biology and Molecular Medicine (CBMM) Program integrates chemical biology and systems biology technologies to develop new therapeutic approaches for the treatment of cancer. Along with research in chemistry and drug discovery and clinical trials, the CBMM includes members interrogating signaling pathways that regulate cell proliferation and survival to identify new targets for cancer therapeutics. Inclusion of basic scientists, chemists, and clinical researchers creates unique opportunities to rapidly translate novel strategies into the clinic, while conversely also increasing the flow of observations from the clinic back to the laboratory for mechanistic testing. 

CBMM members have had a major impact on discerning mechanisms of drug resistance, identifying new vulnerabilities for cancer, developing new small molecules for cancer therapy, and testing new therapeutic and biomarker strategies in early-phase clinical trials. Continued success in these areas, as well as progress in new initiatives, is informed by the Program Specific Aims:

Aim 1: Identify and validate pathways and targets of refractory and metastatic cancer and therapy resistance. CBMM couples system-level unbiased genomics- and high-resolution protein mass spectrometry approaches, as well as novel targeted approaches such as proximity ligation analyses and chemical proteomics, as tools for assessing signaling circuits and for target discovery. Genetic studies are used to validate targets and these approaches define mechanisms of tumor initiation, progression and metastases and modes of acquired drug resistance in refractory cancers. These strategies define and validate new targets for small molecule drug discovery and novel therapeutic approaches for treating patients afflicted with these malignancies.

Aim 2: Characterize mechanisms of action and optimize existing drugs and lead compounds. CBMM members have developed high-quality lead compounds targeting key effectors that drive cancer metastasis and tumor resistance. Using structure-guided design and a battery of biochemical and cell-based assays integrated within a rigorous research-operating plan (ROP), the CBMM advances work to improve selectivity and potency while improving drug-like properties of new analogs. Using iterative medicinal chemistry and guided by structure activity relationships (SAR), and with support of the cancer pharmacokinetic/pharmacodynamic (CPP) developing shared resource, CBMM strives to improve microsomal stability, CYP450 inhibition, protein binding, P-glycoprotein efflux, and PK parameters until criteria for a safety assessment candidate and optimal drug-like properties are attained. Efficacy of improved analogs are tested in validated mouse models and PK parameters are correlated with biologically effective dose by assessing on-target modulation in vivo.

Aim 3: Design and implement therapeutic trials with a precision medicine approach. New therapeutic strategies and new CBMM-generated anti-cancer agents are moved into mechanism-based clinical trials in hematological malignancies and solid tumors. The CBMM faculty are responsible for translating the scientific findings through the design, formulation, and execution of innovative clinical trials. Genomic and proteomic technologies are used to enrich patient enrollment onto clinical trials, and to study drug mechanisms of action and mechanism that drive primary and secondary drug resistance within tumor and blood. The clinical discoveries are then shared in disease agnostic, multidisciplinary forums to foster further collaborations, synergy and advance development of new treatments for our patients.

Impact: CBMM high priority research on melanoma, lung cancer, and cancers in elderly patients have addressed key health disparities within our catchment area and beyond. Moreover, basic and translational research into cancers disproportionally affecting minorities in Moffitt’s catchment area such as triple negative breast and ovarian cancer are being vigorously persuaded. These achievements highlight bench-to-bedside/bedside-to-bench medicine as well as global trials through personalized medicine approaches. Importantly, these efforts have resulted in multiple high-impact publications and updates to NCCN guidelines and Food and Drug Administration (FDA) approvals.

Program Leaders:
Jhanelle Gray, MD
Derek Duckett, PhD

Members:
Melissa Alsina, MD
Rachid Baz, MD
Anders Berglund, PhD
Theresa Boyle, MD, PhD
Julio Jiminez Chavez, MD 
Dung-Tsa Chen, PhD
Alberto A. Chiappori, MD
Christine H. Chung, MD
William S. Dalton, PhD, MD
Ghassan El-Haddad, MD
Zeynep Eroglu, MD
Steven Eschrich, PhD
Jason Fleming, FACS, MD
Peter Forsyth, MD
Heather Han, MD
Eric B. Haura, MD
Rohit Jain, MD, MPH
Haitao (Mark) Ji, PhD
Hung Khong, MD
Nikhil Khushalani, MD
Richard Kim, MD
Rami S. Komrokji, MD
John M. Koomen, PhD
Jeffrey E. Lancet, MD
Eric K. Lau, PhD
Nicholas Lawrence, PhD
James Liu, MD
Justin Lopchuk, PhD
Vince Luca, PhD
Patsy McDonald, PhD
Rutika Mehta, MD, MPH
Andrii Monastyrskyi, PhD
David L. Morse, PhD
Taiga Nishihori, MD
Eric Padron, MD
Sanjay Premi, PhD
Uwe Rix, PhD
Solmaz Sahebjam, MD
David Sallman, MD
Andreas Saltos, MD
Ernst Schonbrunn, PhD
Kenneth H. Shain, MD, PhD
Keiran S. Smalley, PhD
Lubomir Sokol, MD, PhD
Jonathan R. Strosberg, MD
Aik Choon Tan, PhD
Jianguo Tao, MD, PhD
Ahmad Tarhini, MD, PhD
Michael Vogelbaum, MD, PhD
Lixin Wan, PhD
Robert M. Wenham, MD, MS, FACOG, FACS
Yun Seongseok, MD, PhD
Jingsong Zhang, MD, PhD