Taking on a rare childhood disease and triple-negative breast cancer

2022 BIP drug discovery awardees, left to right, Sanjay Malhotra, Ph.D., Ruth Napier, Ph.D., Jonathan Pruneda, Ph.D.

A rare childhood disease and triple-negative breast cancer are the targets of the two projects funded by the drug discovery track of the 2022 OCTRI Biomedical Innovation Program awards.

The BIP awards provide funds, project management, and mentorship to facilitate the development of innovative technologies at OHSU and accelerate their translation to the patients who need them.

UBA5: Screening compounds for therapeutic potential

The OHSU team studying UBA5 has a local connection to the genetic disorder that will help support their research. Raiden Pham was born in Portland on Feb. 26, 2020, and for three months was a healthy baby. At three months, he began to vomit, arch his back, and and delayed developmentally. At seven months, he was hospitalized due to dangerously low weight. For another year, Tommy and Linda Pham pursued care and a diagnosis.               Ultimately, genetic testing at OHSU revealed that Raiden has the rare genetic disorder caused by the UBA5 gene mutation. The Phams launched the Raiden Science Foundation to fund research into UBA5 treatment. Ruth Napier credits the foundation as being “100% responsible for my ability to connect with kids and parents and obtain samples.” (Courtesy photo)

Within the first two years of life, children with the rare neurodegenerative disease called “UBA5” suffer from early-onset epileptic encephalopathy, involuntary movement disorders, epilepsy and often death. UBA5 translational research is urgently needed, as there are currently no treatment options for children with UBA5 disease.

The collaborative, multidisciplinary research team focusing on UBA5 treatment options includes Jonathan Pruneda, Ph.D., Sanjay V. Malhotra, Ph.D., FRSC, and Ruth Napier, Ph.D. These scientists each bring very specific skills to this project: Pruneda is a biochemistry expert in ubiquitin/UBA5 and enzymatic assay development; Malhotra is a leader in chemical biology, high-throughput screening, drug discovery and development; and Napier is an expert in basic and translational research of rare disease and therapeutic approaches.

The team’s goal is to significantly advance our understanding of the disease and open new therapeutic pathways.

Pruneda has developed an assay that Malhotra will use to screen more than 4,300 bioactive compounds including roughly 1,500 FDA-approved drugs, in order to identify small molecules that correct the activity of mutated UBA5 variants. Napier is working with UBA5 patient families to acquire cell lines for studying the effects of corrective compounds.

Triple-negative breast cancer: Moving a small molecule therapy toward clinical trials

Triple-negative breast cancer is an aggressive form of breast cancer that grows and spreads quickly, has fewer treatment options and frequently relapses and metastasizes. There are currently very few options available to treat this cancer.

The Malhotra lab has conducted systematic studies in various triple-negative breast cancer models, leading to the discovery of a small molecule (CET12) that strongly binds to an enzyme implicated in many cancer cells (ENO1) and restrains the cancer cell’s activity. The lab found that treating triple-negative breast cancer cells with this small molecule arrests cell division and leads to cell death.

Extensive studies in the Malhotra lab — including global proteome profiling, in vivo studies in syngeneic mouse models, and patient-derived xenograft modeling — all provide strong merit for further development of the small molecule CET12 for the treatment of triple-negative breast cancer.

BIP program funding will help bring the current research to the point of attracting additional funding and moving the CET12 small molecule toward clinical trials.

Awarded projects and research teams

Abstracts for these projects are available on the BIP website.

Project: Small molecule restoration of UBA5 to treat early-onset neurodegenerative disease

Co-principal investigators:

  • Sanjay V. Malhotra, Ph.D. FRSC
    Professor and Sheila Edwards-Lienhart Endowed Chair in Cancer Research, Cell, Developmental and Cancer Biology, School of Medicine
    Director, Center for Experimental Therapeutics, OHSU Knight Cancer Institute, School of Medicine
  • Ruth Napier, Ph.D.
    Assistant Professor of Molecular Microbiology and Immunology, School of Medicine
    Principal Investigator, VA Portland Health Care System
  • Jonathan Pruneda, Ph.D.
    Assistant Professor of Molecular Microbiology and Immunology, School of Medicine

Project: Developing a novel drug to combat triple negative breast cancer progression through metabolic modulation

Principal Investigator

  • Sanjay V. Malhotra, Ph.D., FRSC
    Professor and Sheila Edwards-Lienhart Endowed Chair in Cancer Research, Cell, Developmental and Cancer Biology, School of Medicine
    Director, Center for Experimental Therapeutics, OHSU Knight Cancer Institute, School of Medicine

Research team

  • Arpit Dheeraj, Ph.D., Postdoctoral Research Fellow, Department of Cancer Research, Cell, Developmental and Cancer Biology, School of Medicine.
  • Dhanir Tailor, PhD., Assistant Staff Scientist ow, Department of Cancer Research, Cell, Developmental and Cancer Biology, School of Medicine
  • Alexander Honkala, Graduate student, Department of Biomedical Engineering, School of Medicine

The Biomedical Innovation Program

By prioritizing commercialization outcomes, the BIP helps position technologies to have the best possible chance of making it to market and improving human health.

The Biomedical Innovation Program is a collaboration of the Oregon Clinical and Translational Research Institute and OHSU Innovates. OCTRI and the BIP are supported by (UL1TR002369) from the National Center for Advancing Translational Science (NCATS) at the National Institutes of Health (NIH).

Additional funding for the BIP is made possible by the University Venture Development Fund and the OHSU Foundation. You may contact Timothy Coffey at coffeyt@ohsu.edu for information on the fund.

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