NCI-Designated Cancer Center

Translational research

Deputy Director's statement

The mission of the NCI-Designated Basic Research Cancer Center at Sanford Burnham Prebys is to understand the biology of cancer and develop impactful therapies through transformative discovery research. Consistent with our mission we are dedicated to translating the discoveries of our outstanding scientists to develop new medicines to treat cancer. More specifically, we strive to advance treatments for deadly cancers through preclinical evaluation and into clinical studies with a special focus on unmet medical needs and underserved communities. With these objectives in mind, our scientists work with the Prebys Drug Discovery Center, our Patient Teams that include clinicians, Philanthropy, and Business Development at Sanford Burnham Prebys to deliver life-changing medications.

Nicholas Cosford, Ph.D.
Deputy Director
NCI-Designated Cancer Center

Cancer Center translational science

Conrad Prebys Center for Chemical Genomics

Largest nonprofit Chemical Screening Center in the US

The Conrad Prebys Center for Chemical Genomics is the Institute's comprehensive center for drug discovery and chemical biology.

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Patient centric focus – disease teams

AML disease team

Team leaders
Ani Deshpande, Ph.D. and Peter Adams, Ph.D.

University of Texas MD Anderson Cancer Center clinician
Gautam Borthakur, M.D.

The AML Disease Team at Sanford Burnham Prebys brings together researchers and clinicians studying hematological cancers to facilitate an ultimate goal of bringing new treatments to the clinic for these deadly diseases. The team meets once a month to discuss relevant research topics, organize the sharing of reagents and resources, and advance collaborative research and grant applications.

Lung oncology disease team

Team leader
Nicholas Cosford, Ph.D.

Moores Cancer Center, UC San Diego clinician
Hatim Husain, M.D.

The Lung Oncology Disease Team at Sanford Burnham Prebys maintains a focus on advancing novel therapies for the treatment of non-small cell lung cancer (NSCLC) and has a funded National Cancer Institute (NCI) P30 Supplement to help drive collaborative research. This team works together to discover new treatment modalities for NSCLC by assessing the interplay of cell death mechanisms, immune response, and autophagic flux in this disease.

Pipeline oncology disease team

Team leaders
Nicholas Cosford, Ph.D. and Michael Jackson, Ph.D.

The Pipeline Oncology Disease Team assembles lead drug discovery researchers to support ongoing translational research at Sanford Burnham Prebys. At each meeting, an individual translational project is discussed in depth allowing the team to assess its merits and unmet needs. Critical issues for each project are identified and addressed with the ultimate objective of promoting new cancer therapies into the clinic.

Pancreatic cancer disease team

Team leader
Cosimo Commisso, Ph.D.

Moores Cancer Center, UC San Diego clinicians
Mayo Clinic clinicians
Scripps Health clinicians

The Pancreatic Cancer Disease Team at Sanford Burnham Prebys brings together researchers and clinicians studying pancreatic ductal adenocarcinoma (PDAC) to facilitate a better understanding of the pathological complexity of the disease with the goal of developing novel therapeutic modalities. The team meets regularly to discuss relevant research topics, organize the sharing of reagents and resources, and to advance collaborative research and grant applications.

Oncology drug pipeline

  DISCOVERY DEVELOPMENT  
Cancer
Indication(s)
Target(s) Drug Type Early
Discovery
Screening &
Hit-to-Lead
Lead
Optimization
In Vivo
POC
Candidate
Selection
Early
Preclinical
Late
Preclinical
Phase 1 Phase 2 Principal
Investigator
Novel/
Repurposed Drug
PDAC RGD Biologic   Ruoslahti Novel
Multiple MEK/ASNS Small molecule     Ronai Repurposed
Brain HDAC/PI3K Small molecule       Wechsler-Reya Repurposed
Lung, Colorectal ULK1/2 Small molecule       Cosford Novel
Multiple LTβR Biologic           Ware Novel
Multiple Myc Small molecule             Wechsler-Reya Novel
Multiple IAPs Small molecule             Cosford Novel
Immunotherapy PSGL-1 Biologic             Bradley Novel
Multiple elF4 Small molecule             Ronai Novel
Hematologic STK3/4 Small molecule               Cosford Novel
Hematologic Shp2 Small molecule                 Tautz/Cosford Novel

Current oncology pipeline spotlights

DEVELOPMENT
Brain cancer

HDAC/P13K
Robert Wechler-Reya, Ph.D.

Studies from the Wechsler-Reya lab demonstrated that histone deacetylase (HDAC) inhibitors and phosphatidylinositol 3-kinase (PI3K) inhibitors synergize to kill cells from medulloblastoma, a highly aggressive pediatric brain tumor. These studies form the basis for a Phase I clinical trial -- run by the Pacific Pediatric Neuro-Oncology Consortium (PNOC) -- to test a combination HDAC/PI3K inhibitor for children with recurrent medulloblastoma and other malignant brain tumors.

Multiple cancer types

MEKi + ANSi
Ze’ev Ronai, Ph.D.

The Ronai Lab has MEKi + ASNSi – a combination of two FDA approved drugs in the pipeline that target the MEK and ASNS (asparagine synthase) pathways and were demonstrated to work in xenograft models of melanoma, and pancreatic cancer. It is currently being evaluated clinically in phase IV pancreatic cancer patients at Oregon Health & Science University (OHSU).

Lung, colorectal and pancreatic cancer

ULK1/2
Nicholas Cosford, Ph.D.
Co PI: Reuben Shaw, Ph.D.

ULK1/2 kinases are essential for the initiation of autophagy, a metabolic process by which intracellular components are recycled to support cellular growth. Several cancer subtypes, including K-Ras-driven cancers, are particularly reliant on autophagy for growth and metastasis. Furthermore, chemotherapeutics, radiation and targeted therapies all upregulate autophagy, indicating that this pathway contributes to therapeutic resistance. We have designed, synthesized, optimized and characterized potent inhibitors of ULK1/2 which are orally bioavailable and reduce tumor cell viability in culture as well as tumor growth in vivo. The lead drug candidate, SBP-1749, is currently undergoing preclinical development in preparation for IND.

DISCOVERY
Cancer immunotherapy

PSGL-1
Linda Bradley, Ph.D.

PSGL-1 is a T cell immune checkpoint inhibitor and immunotherapy target for solid tumors that are resistant to or acquire resistance to current immune checkpoint blockade treatments.

Monoclonal antibodies to block PSGL-1 are also under development.

Multiple cancer types

LTβR
Carl Ware, Ph.D.

“Turning cold tumors into hot tumors” The presence of clusters of lymphocytes within a tumor mass (hot tumor) is a positive indicator of a clinical response to immunotherapy. The clusters, called tertiary lymphoid structures, are organized and capable of mounting an immune response but are often not present in most cancers (cold tumors) including breast, pancreatic and brain cancers. Our goal is to develop drugs that can transform a cold tumors to hot tumors. The Lymphotoxin-beta receptor (LTBR) is the critical signal that promotes the formation of lymphocyte clusters and can eliminate various cancers in animal models. In collaboration with Fair Journey Biologics, we have screened a human monoclonal antibody-based drug that activates LTBR. We recently selected 3 antibodies with the desired functions for clinical development. We are now in funding discussions for an IND-enabling development plan.

Breast cancer

CHK2
Svasti Haricharan, Ph.D.

Currently, 20-40% of patients with ER+ breast cancer, one of the most commonly diagnosed cancers in women around the world, are resistant to standard care endocrine therapies. The only targeted alternative to improve survival for these women is CDK4/6 inhibition, but this therapeutic requires chronic administration, has side effects, and only inhibits cell cycle progression without killing cancer cells. We are working to identify small molecules that can activate an upstream regulator of CDK4/6, which in proof-of-concept mechanistic studies serves to inhibit cell cycle progression and induce apoptosis (cell death) in cancer cells.

Age related disease/cancer

CCF
Peter Adams, Ph.D.

Cellular senescence (a stress induced non-proliferative cell state) is a bona fide tumor suppression mechanism but also a cause of cell and tissue aging. Senescence is caused by a range of cellular stresses and is characterized by an irreversible proliferation arrest and a potent pro-inflammatory phenotype, the senescence-associated secretory phenotype (SASP). Over the long term, as a source of chronic inflammation, SASP promotes tissue aging and disease, including cancer. We recently showed that senescent cells shed fragments of nuclear chromatin into the cytoplasm via a nucleus to cytoplasmic blebbing process, so-called cytoplasmic chromatin fragments (CCF). CCF, in turn, activates SASP. In this project, we will identify small molecule drug-like compounds that inhibit CCF formation and SASP, as lead compounds for preventative interventions of age-related disease, including cancer.

Immunotherapy

SUV39H1
Charles Spruck, Ph.D.

The Spruck Lab’s oncology pipeline project includes SUV39H1, a histone methyltransferase that mediates repressive H3K9me3 marks on chromatin. Their research has found that SUV39H1 plays an essential role in the transcriptional silencing of repetitive elements, including endogenous retroviruses and retrotransposons, in cancer cells. By turning off these silencing factors, SUV39H1 inhibition reactivated repetitive elements in cancer cells, allowing them to fight cancer by turning on the body's natural viral arsenal through a "viral mimicry" phenotype that stimulates antiviral pathways and interferon (IFN) signaling, increasing immunogenicity, decreasing tumorigenicity, and enhancing the response to immunotherapy. Importantly, SUV39H1 was found dispensable for repetitive element silencing in normal cells, indicating a therapeutic window for cancer treatment.

Brain cancer

Myc Inhibitors
Robert Wechsler-Reya, Ph.D.

This project is focused on identifying inhibitors of MYC, a protein that regulates cell growth and is overexpressed in medulloblastoma and many other types of cancer. A screen of 100,000 compounds has identified candidate inhibitors, and these are being optimized to develop drugs that can be used in patients.

Immunotherapy

SIAH
Ze’ev Ronai, Ph.D.
Co-PI's:
Eduard Sergienko, Ph.D.
Steven Olson, Ph.D.
Michael Jackson, Ph.D.

Using innovative tools, the inhibition of the E3 ubiquitin ligases Siah1/2 were shown to be effective for mediating both tumor intrinsic signaling and the remodeling of the tumor microenvironment. This oncology pipeline project from the Ronai Lab is utilizing CTSA (Cell-based Thermal Shift Assays) to map a novel class of small-molecule inhibitors to disrupt Siah1/2 activities in both tumors and their microenvironment.

Skin cancer/Melanoma

GCDH
Ze’ev Ronai, Ph.D.
Co-PI's:
Eduard Sergienko, Ph.D.
Steven Olson, Ph.D.
Michael Jackson, Ph.D.

GCDH (Glutaryl-CoA dehydrogenase) – a component of Lysine Metabolism is a key project of the Ronai Lab: Addiction to select lysine catabolism components were identified in melanoma and screened to identify putative pharmacological inhibitors which led to the discovery of small-molecule inhibitors confirmed in culture and xenograft studies in vivo that promote melanoma cell death.

Multiple tumor types

elF4F Inhibitors
Ze’ev Ronai, Ph.D.
Co-PI's:
Steven Olson, Ph.D.
Michael Jackson, Ph.D.

The eIF4F project of the Ronai Lab – includes the development of small molecule inhibitors that disrupt the translation initiation complex and have been proven to offer effective treatment for a number of tumor types. Initial published studies on SBI-756 indicate it is extended to the mapping and characterization of analogues and components of the eIF4F which are selectively affected.

Leukemia

SHP2
Lutz Tautz. Ph.D.
Nicholas Cosford, Ph.D.

One of several projects in the Cosford Lab include Gain-of-function mutations in the SHP2 (PTPN11) phosphatase that drives leukemogenesis in various juvenile and adult leukemias. Specific small molecule inhibitors developed at SBP target mutant SHP2 in cell culture models of acute myeloid leukemia (AML) and decrease the viability of AML cells. Further development of these novel compounds toward potential therapeutics for the treatment of leukemia patients carrying SHP2 mutations is ongoing.

Multiple cancers

IAPs
Nicholas Cosford, Ph.D.

Apoptotic dysfunction occurs in many malignancies, and resistance to cell death is one of the “Hallmarks of Cancer”. Inhibitor of apoptosis (IAP) proteins suppress apoptotic signaling and their upregulation can contribute to oncogenesis. We have designed and synthesized potent IAP antagonists that reduce the viability of cancer cells both as single agents and in combination with clinically relevant cancer therapeutics. Further characterization and optimization of the lead series with a focus on drug candidate selection is currently ongoing.

Leukemia

STK3/4
Nicholas Cosford, Ph.D.

The serine/threonine kinases 3 and 4 (STK3/4) regulate both cell proliferation and death through their actions on the Hippo signaling pathway. We have designed and synthesized novel STK3/4 inhibitors with nanomolar potency that synergize with the leukemia therapeutic venetoclax to reduce the viability of acute myeloid leukemia (AML) cells in culture and possess favorable pharmacokinetic properties in vivo. This project is currently in lead optimization.