Cancer targets and drug discovery

T32 CA211036

Overview

A strength of the Sanford Burnham Prebys Medical Discovery Institute is the discovery of novel cancer targets and therapeutics, which is our passion. The Institute is also fortunate to be located at the hub of a cluster of over 700 biotech companies in San Diego. These strengths have been combined in this program because the barriers between academia and biotech/pharma are rapidly breaking down with the emergence of a new model where pharma is increasingly looking to biotech and academia for its cancer drug discoveries. As such, there is a need to expose trainees to the exciting opportunities that exist in biotech companies and entrepreneurial research careers.

The goal is to train the next generation of leaders in cancer target discovery and validation, cancer drug discovery, and biomarker development. This two-year training program will provide the skills needed to execute a successful cancer drug discovery program using novel paradigms and state-of-the-art technologies. The program includes training in scientific entrepreneurship specifically focused on new cancer target and drug discovery, as well as research entrepreneurship:
 

  1. Training will focus on critically validating new targets in the context of signaling networks, mechanisms of genetic and epi-genetic regulation, and also on exploring non-traditional targets, for example, targeting components of tumor stroma, which is important for supporting cancer cell growth and providing a barrier to attack by immune cells. The genetic stability of the stroma may also render the putative targets less susceptible to developing resistance
  2. Sanford Burnham Prebys has the technically most advanced and largest chemical library screening program of any academic organization. Our strong expertise in structural-based rational drug design using NMR and X-ray crystallography will provide training opportunities in probe discovery using both approaches
  3. Training will be provided in the use of small molecule probes in cells and preclinical animal models to provide insights into the practical application of drugs to treat cancer, signaling interactions, mechanisms of resistance and potential biomarkers
  4. Given that fewer than 15% of trainees can expect to have a faculty appointment in academia, trainees will be provided with experience in biopharma research as a possible alternate career. Training includes a 2-month cancer biotech internship working with a corporate biotech incubator partner, and will provide a unique entrepreneurial training experience.

Participants in this training program will be provided a solid platform from which to pursue their future cancer-focused research-intensive and research-related careers, they will participate in a formal curriculum of education and training activities.

It is expected that trainees who have completed this program will have received a well-rounded training experience in cutting-edge cancer research of clinical relevance and will be well prepared to embark on a variety of independent research-intensive and research-related careers. While many of the trainees in this program will wish to pursue an academic career path, this program will provide an awareness of a variety of other career paths available.

Program Director

Garth Powis, Ph.D. headshot

Garth Powis, Ph.D.

Dr. Powis is responsible for all managerial aspects of this training program. He works closely with the Steering Committee and the External Advisory Committee. Dr. Powis is committed to the training of our next generation of scientists and has throughout his career been a mentor on multiple T32 training grants at Mayo Clinic, University of Arizona Cancer Center and most recently at MD Anderson Cancer Center.

Program Co-Director
Nicholas Cosford headshot in labNicholas Cosford, Ph.D.

As co-Director, Dr. Cosford will assist Dr. Powis in running the program. He provides additional practical experience of research in both the pharmaceutical and biotech industries, and academic research. He will oversee trainee access to the advanced technological core facilities and will resolve any issue relating to the proper use of these facilities. He will also help oversee scientific aspects of the biotech internships for the trainees to ensure that the projects are high quality with a focus on cancer research, that acceptable plans are in place for a meaningful biotech research experience, and that there are clearly defined and reasonable deliverables for the length of the internship.

Application information

The Cancer Targets and Drug Discovery is an NIH-funded training program. This program accepts both Ph.D. and Ph.D./M.D. postdoctoral researchers.
 

Citizenship requirements

Applicants must be United States citizens, noncitizen nationals or have been lawfully admitted for permanent residence by the time of their appointment.

Non-citizen nationals are people, who, although not citizens of the United States, owe permanent allegiance to the United States. They are generally people born in outlying territories of the United States (e.g., American Samoa and Swains Island). Individuals who have been lawfully admitted for permanent residence must have a currently valid Alien Registration Receipt Card (I-551) or other legal verification of such status.

Individuals on temporary or student visas are not eligible.
 

Prior Ruth L. Kirschstein-NRSA support

The National Research Service Award (now known as Ruth L. Kirschstein National Research Service Award) provides for a maximum of 3 years of post-doctoral funding. Since the CT2 program requires a minimum two-year, NRSA-eligible commitment, eligibility for the program requires that you have had no more than 1 year of prior NRSA post-doctoral support.
 

Faculty mentor

All applicants must identify a faculty mentor prior to having their application reviewed by the Steeering Committee. Please contact the mentor in whose laboratory you wish to complete your research prior to submitting your application. A letter from your mentor expressing interest in having you join his/her group is required to move your application forward.
 

Application requirements

If you would like to be considered for a training position, please identify one or more faculty mentors and complete and submit the following:

  1. Curriculum Vitae
  2. References: Please provide three references who will be able to provide Letters of Recommendation on your behalf.
  3. A one-page personal statement describing the following:
  • Why you are a good candidate for the fellowship.
  • Specific types of research that interest you and relevant experience.
  • What your goals will be during and after the fellowship.

Apply


For any questions regarding the application process, please email T32@sbpdiscovery.org.

Mentor information

The primary goal for the T32 trainees will be to advance their research project. Upon appointment to the Program, the trainee’s mentoring committee will be established. This mentoring committee will include the mentor and another faculty member (often a member of the Steering Committee) chosen to complement the expertise of the mentor and best suited to support the trainee’s research plan. After an initial meeting, each trainee will meet twice annually with the mentoring committee. The committee will review research progress and advise on additional training opportunities. It will also advise on advanced technology-based programs that would be advantageous to integrate in the trainee’s research project. When appropriate, the trainee will also be guided by the mentoring committee to obtain expert technical advice and assistance from other laboratories at Sanford Burnham Prebys. The mentoring committee will advise on the preparation of fellowship proposals and, as the training period progresses, transitioning to an independent career. The Institute’s OETIS facilitates a formal annual Individual Development Planning (IDP) process for all postdoctoral trainees that includes both research project and career components. As part of this training program, the IDP will be reviewed and revised by the trainee in collaboration with the mentoring committee and used as a tool for both the committee and the trainee to openly communicate about goals and achievements.
 

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Mentor bios

Peter D. Adams, Ph.D.

Dr. Adams obtained his PhD from the Imperial Cancer Research Institute in the United Kingdom and was a Postdoctoral Fellow in the Laboratory of Dr. William Kaelin at the Dana-Farber Cancer Institute. He was a member of the Fox Chase Cancer Center before moving to the Beatson Institute, Glasgow UK in 2010 as Head of the Epigenetics Unit. Dr. Adams’ interests are in age-associated epigenetic events that promote aging and age-related diseases, especially cancer, and his research is focused on exit from the cell cycle in the form of senescence, epigenetic control of this process, and hence epigenetic control of aging and cancer. His scientific contributions include mapping the epigenetic landscape of senescent cells, and defining the causes and consequences of this altered landscape. He coined the term “chromostasis” to describe the homeostatic mechanisms that confer epigenetic stability and suppression of age-associated diseases, including cancer, over the life course, the opposing effects of tumor suppressive oncogene-induced senescence and oncogenic activated Wnt signaling in melanocytic neoplasia.
 

Cosimo Commisso, Ph.D.

Dr. Commisso obtained his PhD from the University of Toronto in 2008 and was a Postdoctoral Fellow with Dr. Dafna Bar-Sagi at the New York University School of Medicine. During his postdoctoral research, Dr. Commisso identified the mechanism by which Ras-mutated tumors augment their glutamine supply by boosting macropinocytosis-dependent protein catabolism. His studies demonstrated, for the first time, that oncogenic Ras instructs tumor cells to enhance uptake of extracellular protein via macropinocytosis in order to support cellular metabolism. Dr. Commisso is an active participant in Sanford Burnham Prebys Graduate School of Biomedical Sciences, where he serves on the Admissions Committee and teaches a tutorial: “Bringing the Outside In: Endocytic Mechanisms and Therapeutics” in which students gain insight into how regulation of endocytic pathways can be harness to develop novel therapeutic strategies for human diseases.
 

Aniruddha (Ani) Deshpande, Ph.D.

Dr. Deshpande obtained his PhD from Ludwig Maximilian University, Munich, Germany in 2006. He was then a postdoctoral fellow at the Helmholtz Center for Environmental Health in Munich before moving to the U.S. as an Instructor in Pediatrics in the lab of Dr. Scott Armstrong at Children’s Hospital Boston Harvard Medical School in 2009, and subsequently Memorial Sloan Kettering Cancer Center. His research interests focus on targeting epigenetic pathways for cancer drug discovery. His current research includes studies of epigenetic mechanisms of oncogenesis, and the discovery of novel actionable epigenetic targets for inhibition in heme malignancies. Dr. Deshpande identified specific epigenetic lesions in leukemias with MLL rearrangements and discovered a vulnerability of MLL-leukemias to small-molecule inhibition of the histone methyltransferase DOT1L. He regularly teaches modules in the Sanford Burnham Prebys Graduate School of Biomedical Sciences foundation course “Molecules to Systems” (M2S).
 

Brooke Emerling, Ph.D.

Dr. Emerling was a postdoctoral fellow with Dr. Lewis Cantley at Harvard Medical School/BIDMC after obtaining her PhD in 2007 from Northwestern University (Faculty mentor Navdeep Chandel). She was an Instructor after the Cantley lab moved to Weill Cornell College Medicine in 2013. Dr. Emerling is investigating the role of the phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) family of enzymes, and previously found that PI5P4K is required for the proliferation of a subset of cancer cells in breast cancer and that PI5P4K deficiency restricts tumorigenesis in vivo. Dr. Emerling is currently conducting studies targeting p53 mutant HER2 amplified breast cancers through inhibition of PI5P4K.
 

Malene Hansen, Ph.D.

Dr. Hansen obtained her PhD at Copenhagen University, Denmark, and was a postdoc with Dr. Cynthia Kenyon (UCSF) until 2007, when she started her lab at The Institute. She is Associate Dean for Student Affairs of the Sanford Burnham Prebys Graduate School of Biomedical Sciences, and Faculty Advisor for Postdoctoral Training. Her research focuses on understanding the molecular mechanisms of aging, with a special emphasis on the cellular recycling process autophagy. Her work demonstrated that autophagy is a critical factor in determining lifespan in several conserved C. elegans longevity models and has identified new autophagy regulators in both C. elegans and mammalian cells. Dr. Hansen also discovered that the proto-oncogene ILK is a conserved longevity gene, and has elucidated molecular mechanisms by which the S6K oncogene mediates longevity in C. elegans. Dr. Hansen and her group are currently investigating the role and spatiotemporal regulation of autophagy during organismal aging and the mechanisms by which the tumor suppressors STK3/STK4 regulate autophagy in mammalian cells. Her mentoring skills were recently recognized when she received the 2017 National Postdoctoral Association Garnett-Powers & Associates, Inc. Mentor Award.

 

Elena Pasquale, Ph.D.

Dr. Pasquale earned her PhD in biology from the University of Parma. Her research focuses on receptor tyrosine kinases of the Eph family and their ligands, ephrins, which represent an important cell communication system in cancer. Binding to ephrin ligands on the surface of neighboring cells induces canonical signaling involving receptor clustering, autophosphorylation of tyrosine residues, and kinase activity-dependent downstream signaling. Ongoing efforts in Dr. Pasquale’s laboratory focus on the development of agents to target Eph receptors that can be used for research and translational applications. She has developed cyclic peptide antagonists that bind to the EphA4 receptor with nanomolar affinity. Such molecules can be used to specifically disrupt protein-protein signaling to modulate Eph receptor activity.
 

Ze’ev Ronai, Ph.D.

Dr. Ronai earned his PhD in Tumor Immunology from the Hebrew University of Jerusalem, Israel. He trained as a postdoctoral fellow in molecular biology and viral carcinogenesis at Columbia University. Dr. Ronai was awarded a T32 postdoctoral training grant while at Mount Sinai School of Medicine, which he directed until his move to Sanford Burnham Prebys in 2004, where he led a different transdisciplinary NCI T32 training program. His research is directed towards understanding the regulation and function of stress response signaling pathways, in particular cooperation between ubiquitin ligases and protein kinases in the regulation of hypoxia, ER stress, and the cell cycle.
 

Guy Salvesen, Ph.D.

Dr. Salvesen obtained his PhD in biochemistry from Cambridge University UK. He conducted postdoctoral research at Strangeways Laboratory and MRC Laboratory of Molecular Biology in Cambridge, followed by further postdoctoral training at the University of Georgia. Dr. Salvesen joined the Institute in 1996 from Duke University and is Dean of Sanford Burnham Prebys Graduate School of Biomedical Sciences. In this capacity, Dr. Salvesen sets goals and processes for the graduate school, collaborates with Dr. Diane Klotz in postdoctoral training, and oversees mentoring of Research Assistant Professors. Dr. Salvesen’s research focuses on the central role enzyme pathways play in the life and death of normal and cancer cells.
 

Alexey Terskikh, Ph.D.

Dr. Terskikh obtained his PhD in 1997 from University of Lausanne Institute of Biochemistry, Switzerland and was a postdoctoral fellow at Stanford University School of Medicine with Dr. Irv Weissman until 2002 when he joined the Brain and Mind Institute, Swiss Polytechnic School, Lausanne as Assistant Professor. His early work identified the existence of common genes, products and pathways that operate in both hematopoietic and stem cells, and his laboratory focuses on the mechanism of self-renewal and differentiation of stem/precursor cells. Dr. Terskikh and his group also defined the molecular mechanisms involved in Sox2 function in neural stem cells and glioblastoma cancer stem cells.
 

Carl Ware, Ph.D.

Dr. Ware received his PhD in Molecular Biology and Biochemistry from the University of California, Irvine in 1979. With Dr. Tim Springer at Dana-Farber Cancer Institute, he developed monoclonal antibodies that allowed him to discover several membrane proteins associated with T cell function. In 1996, he became Head of the Division of Molecular Immunology at the La Jolla Institute for Allergy and Immunology, and in 2010 was recruited to Sanford Burnham Prebys as Director of the Infectious and Inflammatory Diseases Center. His work has led to the discovery of several members of TNF cytokine superfamily and their signaling circuitry. Dr. Ware has founded a biotech company to help translate his discoveries into new therapies for cancer, infectious and autoimmune diseases.
 

Robert Wechsler-Reya, Ph.D.

Dr. Wechsler-Reya received his PhD from the University of Pennsylvania and completed fellowships in molecular oncology at the Wistar Institute, Philadelphia, PA, as well as a fellowship in neural development at Stanford University. He was a member of the faculty at Duke University before joining the Institute in 2010, where he is Director of the Tumor Initiation and Maintenance Program. His research focuses on the signals that control growth and differentiation in the cerebellum, and how these signals are dysregulated in the brain tumor medulloblastoma. Recently, Dr. Wechsler-Reya and his group have been developing new models of medulloblastoma and are using them to test novel therapeutic approaches. He has taught modules for the Sanford Burnham Prebys Graduate School of Biomedical Sciences M2S course.
 

Garth Powis, D.Phil.
 
Nicholas Cosford, Ph.D.

Trainee information

During the first year of the training program the primary goal for the T32 trainees will be to advance their research project. By the end of the calendar year, each trainee is expected to establish their mentoring committee. Trainee progress for the first year of training will focus on advancing their research project and will be evaluated through (1) general evaluations from their preceptors and mentors; (2) performance and participation in program coursework and professional development activities; (3) research progress towards publications in scholarly journals or patents/licensing agreements indicative of research progress; and (4) participation in the broader immunology community through presentations at local, national, and/or international meetings.

The participants will participate in a formal curriculum of education and training activities. Some of these activities have been uniquely developed for this program, others are available to all Sanford Burnham Prebys trainees but will be a required component of this Program, and other additional activities will not be required but will be strongly encouraged to enhance the training experience based on individual research and career goals.

Predoctoral students will participate in the program curriculum alongside his/her postdoctoral colleagues. It is expected that early exposure of the predoctoral student to the opportunities and information traditionally only available to postdoctoral trainees will result in a more-informed Ph.D. in the biomedical sciences who will be able to select a career goal-appropriate postdoctoral training experience, move directly into a career position that does not require postdoctoral training, or possibly move directly into a career in academics without pursuing postdoctoral training, as envisaged in the NIH Director's Early Independence Awards (DP5), and reduce the amount of time often taken to determine and pursue career goals.

It is expected that trainees who have completed this Program will have received a well-rounded training experience in cutting-edge cancer research of clinical relevance and will be well prepared to embark on a variety of independent research-intensive and research-related careers in fundamental and translational oncology.
 

Current NRSA postdoctoral fellows

Corey Bretz, Ph.D.
Mentor: Peter Adams, Ph.D.
Research project: Research project: Discovery and validation of the H4K20me3 demethylase as a cancer drug target

Dr. Bretz is screening for a histone demethylase that removes H4K20me3, and will validate the demethylase as a cancer drug target. Thus far, the he has conceptualized the screen, has generated Cas9 inducible cancer cell lines, has established immunofluorescent assay for H4K20me3, and is generating Suv420H2 KO in the Cas9 inducible cancer cell lines. He will design and execute all experiments, analyze the data, and write the manuscript.
 

Nicole Bakas, Ph.D.
Mentor: Nicholas Cosford, Ph.D.
Research project: The design, synthesis and characterization of small molecule autophagy modulators for the treatment of cancer

Dr. Bakas received her PhD in 2017 under the supervision of Prof. Michael Pirrung in the Department of Chemistry at the University of California, Riverside. She is currently working on the synthesis and optimization of novel small molecule autophagy modulators
 

Scotty Cadet
Mentor: Garth Powis, D.Phil.
Research project: MPI Knockdown in combination with mannose supplements enhances EGFR-targeted therapy

Mr. Cadet is a graduate student working on his PhD in cancer biology. Mr. Cadet has a background in understanding environment that promotes genome integrity in stem cells. In his current project, he is interested in understanding the effect of hypoxia on genome stability in lung cancer cells as a way to reduce mutation load that give rise to drug resistance in lung cancer therapies. Thus far, he has demonstrated in vitro that lung cancer cells under hypoxia have low levels of phosphorylated Rad51, 53bp1 and H2Ax, which are key DNA repair damage response players, without significant changes in ataxia telangiectasia-mutated (ATM) which is responsible for phosphorylating Rad51, 53bp1 and H2Ax. Further, he has shown that hypoxic lung cancer cells evoke endoplasmic reticulum (ER) stress by the high levels of the ER associated degradation (ERAD) protein, EDEM1, suggesting a degradation mechanism for hypo-glycosylated protein. Finally, he has shown the knockdown alone of MPI is not enough to restore glycosylation and/or DNA repair activity. Next, he is interested in evaluating the knockdown of MPI in combination with mannose supplements in lung cancer cells to restore protein glycosylation of hypoxic cancer cells and increase DNA repair protein activation.
 

Sujita Khanal, Ph.D.
 

Former NRSA Postdoctoral Fellows

Luz Marina Meneghini, Ph.D.
Mentor: Francesca Marassi, Ph.D.
Research proposal: A major challenge in cancer therapy is the tendency of cancerous cells to leave a primary tumor site and metastasize to different vital organs

It is still not well understood the molecular mechanisms that govern this process. However, it is well known that the presence of abundant plasma and serum proteins, such as vitronectin, plays an essential role in maintaining homeostatic processes including cell migration, adhesion and angiogenesis, and are exploited by malignant cells to spread and proliferate. Vitronectin is an abundant adhesive glycoprotein in blood plasma and is found associated with different extracellular matrix sites, the vessel wall, and tumor cells. It is is found as two molecular forms: a one-chain form of 75 kDa (Vn75) and a clipped form (Vn65+10) composed of two chains (65 and 10 kDa) held together by a disulfide bridge. The predominant form of Vn in plasma is monomeric, while multimeric forms are found attached to the extracellular matrix. Plasma vitronectin is a structurally pliable molecule that is composed of 459 residues with several distinct binding domains. Each domain interacts with specific molecular partners to modulate different biological processes. The N-terminal somatomedin B (SMB) domain (1-43) binds to the plasminogen activator inhibitor 1 (PAI-1) and urokinase receptor (uPAR), which plays an important role in wound healing. Next to the SMB domain is the RGD site, which is an integrin binding region involved in cell adhesion and migration. Dr. Meneghini used solution and solid-state Nuclear Magnetic Resonance (NMR) Spectroscopy and ELISAbased binding assays to identify which residues are required for the protein−protein interactions between Vn and IGF-2. Given the potential significance of Vn and IGF-2 in various cancers, my project focuses on identifying the specific regions within Vn that mediate binding to IGF-2 by utilizing both structural and functional methods available.
 

Szu-Wei Lee, Ph.D.
Mentor: Cosimo Commisso, Ph.D.
Research project: Research project: Discovery and validation of novel metabolic targets in pancreatic cancer

Dr. Lee has discovered that pancreatic cancer cells employ macropinocytosis as an adaptive response to glutamine metabolism-based targeting. In collaboration with the SBP Functional Genomics Shared Resource, she performed a high-throughput kinome-wide siRNA screen to identify genes critical for orchestrating this response. She identified 22 hits from the primary screen and performed validation using secondary screening strategies, narrowing down the targets to four major modulators. Dr. Lee explored the mechanistic underpinnings of these macropinocytosis modulators with the goal of establishing combination therapies using these kinases.