The vision of the DCI leadership in reorganizing two former CCSG programs—Structural/Chemical Biology and Experimental Therapeutics—into the new Developmental Therapeutics, was to create a program that contains expertise along the drug development continuum, from solving structures of new targets, generation of chemically diverse libraries, hit to lead optimization, development of novel tumor vaccine platforms, and discovery of new technologies to improve drug delivery.
The DCI leadership considers the Developmental Therapeutics Program to be the cornerstone of drug development and testing within the cancer institute, (Figure 1). There are active inter-programmatic collaborations and coordinated efforts to share information and best practices with investigators involved in developing therapeutics in other programs. Lacking a clinical component, the program leadership and members have developed productive inter-programmatic collaborations with clinical investigators in disease oriented programs including Solid Tumor Therapeutics and Women’s Cancer to transition novel therapeutics into the clinic.
Leadership Bio: Neil Spector, MD
Neil Spector, MD, is the Program Director and Sandra P. Coates Associate Professor of Cancer Research, Department of Medicine. He is a leading authority in the application of translational research to the development of tumor targeted therapies.
Prior to joining the faculty at Duke in 2006, he was the director of Translational Cancer Research at GlaxoSmithKline from 1998-2006. During that time, he led the development of six new chemical entities and biological therapies into the clinic, two of which, lapatinib and nelarabine, were eventually FDA-approved. His work on molecular mechanisms of therapeutic resistance provided the scientific rationale for a clinical development program that led to an additional FDA approval for lapatinib in combination with the aromatase inhibitor letrozole as a first-line treatment for advanced stage HER2+/estrogen receptor positive breast cancers.
Spector has played a pivotal role as a co-investigator tasked with generating a translational research strategy to guide the development of targeted therapies funded through two multi-investigator grants from the DOD BCRP. He continues to engage scientists not previously involved in cancer research, leveraging their expertise to enhance the cancer research efforts at Duke, as illustrated by a recently awarded partnering PI grant through the DOD BCRP with a newly recruited program member Michael Therien, PhD (Department of Chemistry, School of Arts and Science).
Mentoring medical oncology fellows and Pharmacology/Molecular Cancer Biology graduate students remains an important aspect of Dr. Spector’s commitment to education. In 2010-2011 he was awarded the Wendell Rosse Teaching Award by the Duke hematology/medical oncology fellows for outstanding teaching and mentorship. In 2010, he was selected by his peers as a Komen Scholar, a multi-disciplinary group of the top breast cancer researchers in the world.
The program is led by Neil Spector, MD, who meets with DCI Director Michael Kastan, MD, PhD and other program leaders on a bi-monthly basis as part of the DCI Executive Committee, where program updates are discussed.
The diversity of research interests within the newly formed program, from structural analysis of molecular targets to drug delivery systems, presents both a challenge and an opportunity to leverage the expertise that now exists along the continuum of drug development activities to advance small molecules and biologics targeting molecular targets that were identified and credentialed by DCI investigators or external collaborators. With this goal in mind, we organized the program into three research focus groups (RFG) anchored around central thematic areas that reflect the expertise of our members, and encompass key components along the spectrum of developmental therapeutics research activities.
The importance of gaining structural insight into molecular targets and their structure-activity-relationships (SAR) in order to inform the rational design of drugs and creation of structurally diverse chemical libraries for screening, was the genesis for the Structure and Chemical Biology Focus Group. Structures of attractive cancer targets have been solved by program members who have forged new intra-programmatic collaborations to create diverse chemical libraries based on insight into SAR, and development of high through up screening platforms for screening chemical libraries.
A separate core competence required for drug development involves the design of chemically diverse libraries and development of high or low throughput screening platforms, which falls under the domain of the Molecular Targets and Therapeutics Focus Group, which has benefitted from new program recruitments with expertise in designing diverse chemical libraries and development of innovative high throughput screening platforms. The Therapeutics aspect of this focus group not only includes small molecules but also biologics including tumor vaccine and therapeutic aptamers. Small molecules compounds may demonstrate potency in vitro, but frequently fail in the clinic due to bioavailability and pharmacokinetic liabilities.
We are fortunate to have recruited new members from Schools of Biomedical Engineering and Arts and Sciences (Department of Chemistry) who have developed proprietary technologies to improve solubility and drug delivery to tumors. These members comprise the Drug Delivery Focus Group.
The focus groups meet quarterly to discuss research projects and concerns that need to be addressed by the program or DCI leadership. In addition, we have a monthly program seminar series where members present their work in progress, and external speakers talk about research topics aligned with the research interests of the program. An annual retreat provides additional opportunities for members to hear about research conducted in the program and a venue for trainees to present their work.
The programmatic goal is to build within the DCI a core competence to take cutting edge targets such as oncogenic drivers and define novel therapeutics in the form of small molecules or biologics. To accomplish our goal we have organized the program around three programmatic research aims:
1. Structural and Chemical Biology
2. Drug Discovery and Development
3. Drug delivery and formulation
Structural and Chemical Biology
Molecular Targets and Therapeutics
Improved Drug Delivery Systems
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