The Molecular Therapeutics Program has highly integrated basic science and translational components in four areas: structural biology; drug discovery, development and delivery; pharmacology and pharmacogenomics; and oncogenic signaling. The program’s objective is to combine these elements to develop novel therapeutics and to infuse Lineberger clinical trials with strong scientific rationale and correlative science. The program is a major component of the Center’s UCRF strategic plan for Drug Discovery and Delivery and hence will continue to expand over the next CCSG cycle. The UCRF resources have led to the creation of requisite Cancer Center infrastructure to make possible the goal of this program: the discovery and development of novel therapeutics to directly benefit human cancer patients.
The Molecular Therapeutics Program seeks to develop novel therapeutics for cancer treatment. The program is comprised of investigators whose work relates to questions of:
- Structural biology: This is comprised of investigators with expertise in X-ray crystallography, NMR and computer modeling.
- Drug discovery/development/delivery: This includes investigators with expertise in screening and small molecule medicinal chemistry, drug testing in animal models and the development of novel formulations and vehicles (nanoparticles, viral delivery).
- Pharmacology and Pharmacogenetics: This includes investigators studying the pharmacology and pharmacodynamics of novel therapeutics, and well as investigators focusing on the genetics of drug toxicity in humans.
- Oncogenic Signaling: This includes investigators with expertise in signaling networks involving receptors, GTPases, protein kinases and phospholipases.
These components of the program mutually interact with one another, as well as with other Cancer Center programs. Through these interactions, nearly all steps critical to the discovery and development of promising therapies are now available to Cancer Center members:
To find and validate new targets for cancer therapies. This is accomplished by several methods including candidate identification through tumor genetic analyses, proteomic screens and high-throughput forward genetic (e.g. siRNA) screens.
To develop small molecule compounds to modulate identified targets.This is facilitated by structural biologic analysis, computer modeling, focused and high-throughput compound screening and medicinal chemistry to move from hit to lead and beyond.
To test potential agents in vitro and in faithful animal cancer models. This relies on investigator-initiated testing on optimized in vitro systems, usually followed by further testing in the animal models core for orthotopic cell line and human tumor sample xenograft testing and the MP1U for testing in faithful genetically engineered murine models (GEMMs).
To provide better delivery and formulation of promising therapeutics. This relies on novel surface chemistry and nanoparticle synthesis through UNC-discovered methodologies such as Particle Replication in Non-wetting Templates (PRINT); and the use of novel viral vectors. Others are working on devices based on physical science precepts that will provide new delivery modalities. In particular, studies from this area will be targeted for funding and rapid translation, with UNC-based delivery concepts leading to ongoing commercialization and clinical trials in humans.
To assess agents' pharmacology (PK), pharmacodynamics (PD) and efficacy; and understand host genetic features that predict toxicity. These efforts have been facilitated by the recent recruitment of program members Howard Mcleod and William Zamboni. Dr. McLeod is a national leader in pharmacogenomics, overseeing several large candidate and genome-wide studies of host features associated with drug response and toxicity. Additionally, PD studies have been facilitated by the generation of novel imaging agents developed by program members.
Through collaboration with industry and other private-public research institutions, to perform compound lead optimization, rodent toxicology and commercialization. As the scope of these last steps of drug development necessarily requires collaboration with non-University entities, members of the Program are encouraged to interact with industry to facilitate therapeutic development. Toward this end, the Cancer Center supports the pursuit of intellectual property for member discoveries and facilitates the negotiation of material transfer agreements and contracts with industry up to and including UNC start-up companies. In this regard, the Cancer Center benefits from a dedicated, recently recruited, and UCRF-supported JD with expertise in patent law, out-licensing and industry collaboration and a new program (NC BioStart) for commercialization being developed jointly by the Cancer Center and the UNC CTSA.
Dr. Gary Johnson, program co-leader for the last seven years, is the Chair of Pharmacology and is renowned for his research defining MAPK signal transduction pathways and their biologic significance. Dr. Norman Sharpless, program co-leader for the last two years, is a clinically active physician-scientist with a national reputation in translational research with particular expertise in murine cancer models.