Translational Experimental Therapeutics

Current Research Focus

SJCI’s TETR is an interdisciplinary program, uniting diversified scientists and clinicians specializing in a wide range of fields, including experimental therapeutics (drug discovery), nanoparticle, cancer biology, biochemistry, immunology, molecular pharmacology, medical oncology, and surgery. Over the past three years, our program has already taken on several translational experimental therapeutic projects for cancer and neurodegenerative diseases. Several research projects have matured to the stage of preclinical IND. These discoveries hold promise for many cancers, both common and rare, and represent the full spectrum of therapeutic modalities including experimental therapeutics, drug delivery, and combination therapy. Our unique skills and collaborations have made SJCI’s TET research program successful in the development of novel therapeutics to address clinically challenging problems.

Our program applies the following methods to maximize the success of the translational projects in a quick and efficient manner including:

• Informed and levelheaded decision making under tight timelines
• Minimizing costs and time and maximizing success by starting with innovative project design
• Multidisciplinary background allows for effective communication between chemistry and biology teams
• Emphasizing a collaborative team environment internally and externally to reach goals more effectively
• Fostering positive energy and respect among team members

To ensure that the most promising ideas are funded, we submit grant applications which are subjected to a competitive peer-review process modeled on that of the National Institutes of Health, Department of Defense, and other private foundations. The TET research program welcomes research projects for therapeutic development in any type of cancer and particularly favors collaborative research projects in which multiple investigators with different expertise focus on a specific type of cancer or treatment modality.

Active In-house Translational Research Projects:

• Disease Areas: Triple Negative Breast Cancer, Glioblastoma, SARS CoV-2 and Alzheimer’s Disease

Active Collaborative Translational Research Projects:

• Disease Areas: Diffuse Intrinsic Pontine Glioma, Medulloblastoma, ER+ Breast Cancer Resistance, metastatic castration resistance Prostate Cancer, Addiction

Triple Negative Breast Cancer:

Clinical Significance:  Breast cancer (BC), a leading cause of death in women worldwide, comprises three major pathological subtypes: ER+, HER2+, and triple-negative Breast Cancer (TNBC). TNBC represents 15–20% of breast cancer cases but accounts for 25% of deaths. TNBCs are highly heterogeneous and aggressive diseases. Gene analysis indicates that 70–80% of TNBC are of the highly aggressive subtype, Basal like Breast Cancer (BLBC, TNBC), that will initially respond to chemotherapy but eventually develops resistance, metastasis, and post-surgical re-occurrence. This poor outcome derives from the heterogeneous nature of the disease, coupled with a lack of biomarkers that are necessary for therapy. There is an urgent need to improve our understanding of the molecular basis for BLBC, to discover effective therapeutic targets to improve the outcome in patients.

Our Approach:  In recent years, genetic analyses have helped delineate the molecular landscape of TNBC. Prior studies have revealed various mutations in TNBC with many arising in tumor suppressors, genes that typically regulate cell growth but can result in cancer if lost through mutation. Despite these findings, there remain few treatments to target tumor suppressor loss in TNBC. Specifically, the retinoblastoma (RB) tumor suppressor is frequently lost in TNBC, occurring in an estimated 30% of cases. Typically, the RB tumor suppressor plays a key role in cell cycle regulation. However, if mutated, the RB tumor suppressor cannot inhibit cell cycle progression, contributing to tumorigenesis. While there have been recent developments in treatments for hormone-receptor-positive and some subtypes of TNBC with CDK 4/6 inhibitors, these therapies rely on an intact RB for success. Due to the high frequency of RB loss and current absence of effective therapies, efforts to develop selective therapies for RB loss in TNBC are needed. We have developed novel experimental drugs that effectively kill TNBC cells with RB loss.

Glioblastoma Multiforme:

Clinical Significance:  Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults. Despite advances in understanding the molecular mechanisms underlying GBM tumorigenesis, most current targeted therapies have proven ineffective and temozolomide (TMZ) has remained the cornerstone of GBM treatment. Radiation and TMZ followed by adjuvant TMZ show significant improvement in GBM patient survival, but all tumors ultimately recur, leaving median survival at only 12-15 months.

Unfortunately, TMZ treatment is primarily effective only in late stage GBM tumors, when the tight junctions around the BBB have degraded and become “leaky”; in early stage GBM, the tight junctions around the intact blood brain barrier (BBB) prevent adequate TMZ dosing at the tumor site. Increasing the dose to increase efficacy is not an option, due to the severe dose limiting myelosuppressive toxicity, unrelated to the CNS. Furthermore, over 50% of GBM patients treated with TMZ do not respond to the therapy due to intrinsic, MGMT driven resistance, and those that do respond eventually develop TMZ-resistant recurrent tumors. There is clearly a need for alternative chemotherapeutic options in the clinic. The development of a new class of TMZ-like analogs, with improved brain-to-plasma ratios (which might minimize the myelosuppressive toxicity), encapsulated into tumor targeted nano-carriers that maximize their therapeutic efficiency (and can bypass the intact BBB) can address these persistent clinical limitations.

Our Approach: Our lab has developed and synthesized a series of novel TMZ analogs, designed to have improved blood to plasma ratios. These analogs were structurally characterized, evaluated, and then ranked according to their efficacy and brain permeability. During this process we identified an initial lead compound named VMY-TP9. Our lead TP9 has a greater brain-to-plasma ratio (>3-fold) than TMZ, when administered both intravenously and orally. TP9 showed promising inhibitory activity in tumor cells that are highly TMZ-resistant (T98G) and produced DNA damage effects for a prolonged period. In an initial GBM animal model study, our lead TP9 was well tolerated (no change on body weight) and showed a slightly better neutrophil count (bone marrow toxicity) in mice at the tested dose compared to TMZ, while showing similar tumor growth inhibition.

SARS CoV-2:

The COVID-19 pandemic is an ongoing medical health emergency worldwide, and significant efforts are underway to develop detection tools, treatment options, and prevention modalities to manage it. Similar to many other viruses, the SARS-CoV-2 virus binds to and enters into a host cell to hijack its cellular machinery to proliferate and spread infections. Studies have shown that SARS-CoV-2 uses the spike protein (SP) protruding from its surface, to target and bind to the ACE2 protein located on the membrane of human lung tissue. Before the virus can fully enter and infect the host cell, the spike protein is also cleaved by other proteins on the cell surface, furin and TMPRSS2.

Blocking viral entry into host cells is one of the most effective ways to prevent infection and serious illness. Anti-SARS-CoV-2 vaccines and neutralizing antibodies have been developed to block the infection by the virus, but they may not be sensitive to new viral strains appearing worldwide, and (for neutralizing antibodies) they unfortunately show only limited potency. Furthermore, antibody mediated therapies are financially burdensome to both patients and the healthcare system. Considering these issues, the preferred approach of pharmaceutical development is an orally bioavailable small molecule targeting the spike protein. A small molecule would have many advantages over vaccines and ‘biologics’: small molecule pharmaceuticals are effective, affordable and easy to administer. Using advanced computational methods (molecular dynamics and structure- guided drug-binding analysis), we have already identified initial hits that bind to the SARS- CoV-2 spike glycoprotein.

Our present work is mainly focused on prioritizing the best natural compounds from these hits, with ideal chemical profiles for preclinical and clinical efficacy and potency. To achieve these goals, we will measure the Drug/ACE2 interaction inhibition in invitro assays. Mapping the mechanism of action of these compounds will lead to the development of new therapeutics for SARS-CoV-2. Our approach is a highly cost-effective method of rapidly identifying natural small molecule inhibitors that can efficiently bind to the SARS-CoV-2 spike protein and prevent COVID-19 infection.

Alzheimer’s Disease:

Clinical Significance:  Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which affects about 5.5 million people in the United States and 40 million worldwide. There is an urgent need to develop new therapeutic approaches as the current FDA approved medications have no effects on the progression of the disease. it is estimated that by 2050, 12 million people in the United States will have AD (Alzheimer’s, 2015). Accumulation of amyloid-b (Ab) protein and hyper-phosphorylated tau protein are critical events in the pathogenesis of AD. Pathological tau aggregates eventually form toxic neurofibrillary tangles (NFTs), characteristic of AD and other neurodegenerative tauopathies.

Our Approach:  Many drugs have been developed to target Ab and NFTs directly, and all have failed in the past few decades. We are focused on developing new drugs to target high impact early targets that have roles in developing Alzheimer’s: CDK5/p25. The abnormally active CDK5 protein plays a major role in the over-activation of tau and is the most damaging step in NFT formation. Cyclin dependent kinase-5 (CDK5) inhibitors an attractive and innovative approach towards preventing tau hyperphosphorylation.

We performed a high-end computer aided drug design virtual screen to identify CDK5-p25 inhibitors. We identified pockets on either CDK5, p25, or at the interface of the CDK5-p25 complex and employed a virtual screening (structure and ligand based) protocol to identify suitable binders in the pockets. This is the first time where we introduced six virtual screening protocols into the CDK5/p25 complex to identify several highly selective and potent inhibitors that inhibit p25 activity.

Our Supporters

We would like to thank the below funding supporting sources in support of our research. Without this support, we would not be able to advance in developing novel lead experimental drugs for treating Cancer and Neurodegenerative disease.

Donations:

If you would like to make donations, please make checks payable to:

Saint John’s Cancer Institute TET Research Program
2200 Santa Monica Blvd
Santa Monica, CA 90404

News and Events:

UAH’s Baudry Lab part of half-million-dollar efforts to target COVID with drug therapies

Dr. Venkata Maidhar Yenugonda, M.Phil, Ph.D., Director, Drug Discovery and Nanomedicine Laboratory, lends his scientific expertise as part of the SARS CoV-2 research grant recently awarded by St. John’s Cancer Institute.
See full story at uah.edu/news
JUL 29, 2021 | Jim Steele

2021 Conferences and Invited Speakers:

Invited Speaker
3^rdInternational Conference on  PHARMA R&D-2021 (Feb 22, 2021)

Keynote Guest Speaker
8th International Conference on Brain Disorders and Therapeutics
London, UK
September 15-16, 2021

Poster Presentation
47^th Annual Meeting of Korean Cancer Association and 7 ^th International Cancer Conference

Career Opportunities:

The TET research program is always looking for talented and enthusiastic individuals at all levels who are interested in becoming a part of our team developing new therapeutics for unmet medical needs.

We currently have openings for the following opportunities:

• Student Interns and Research Associate positions that are open currently.

To apply, please contact:

Venkata Mahidhar Yenugonda , M.S., Ph.D.
Program Director
yenugondav@providence.org
vmy@jwci.org