Owens Foundation awards projects for cancer and Alzheimer’s research

The William and Ella Owens Medical Research Foundation is awarding $1.5 million to UT Health San Antonio to support research projects that address brain cancers, pancreatic cancers, Alzheimer's disease and childhood cancers.

This year, the foundation will fund eight research projects from UT Health San Antonio investigators. This year's recipients of the award and a description of their projects are as follows:

Nicolas Honnorat, PhD, professor in the Department of Population Health Sciences with a joint appointment at the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases.

Project title:Neuroimaging models of tau and beta-amyloid accumulation in Alzheimer's Disease

Description: In this project, Honnorat's team proposes to process a large set of brain scans to model the accumulation of amyloid beta and tau neurofibrillary tangles observed in Alzheimer's Disease. The overarching goal of this work is to replicate and improve current models for dementia onset and disease progression and, more specifically, the spread of neurofibrillary tangles and their interaction with amyloid beta plaques. They will achieve a large sample size by leveraging advanced statistical harmonization methods to combine brain scans released by independent neuroimaging studies. The project will produce a data set specifically designed to conduct additional research and apply for extramural funding in the future with a long-term goal of guiding the development of therapies that slow down the progression of Alzheimer's Disease.

Maria Gaczynska, PhD, associate professor in the Department of Molecular Medicine.

Project title:Novel proteasome-activating compounds for treatment of Alzheimer's Disease

Description: Alzheimer's disease (AD) ranks among the most socially costly diseases, devastating for the patients and their caregivers. This debilitating and lethal malady affects 10% of older adults and is marked by progressive memory loss and other critical mental functions. The loss is caused by neurodegeneration, when the cells in patients' brains stop working and die after becoming overloaded with toxic aggregates of proteins. There is no cure for AD. Available drugs, including the controversial recently approved ones, target primarily the most prominent toxic protein, and at the best temporarily improve symptoms. Gaczynska's project proposes to implement a more holistic approach to the treatment of AD. Instead of removing a single poison, the research team aims to prevent a buildup of all the poisonous aggregates. Accumulation of the aggregates is the effect of lost proteostasis, or the balance between protein synthesis and disassembly. The giant enzyme proteasome is a critical part of protein removal machinery and neurons are especially dependent on its function. The proteasome is weakened during normal aging but still upholds proteostasis. Unfortunately, in AD the proteasomes in neurons become entangled in a deadly vicious cycle, unable to keep up with protein degradation, the proteins accumulate, aggregate and poison the proteasomes and neurons even more. The team proposes to break the cycle and boost the activity of the proteasome to help maintain proteostasis. The proposed work is premised on previous successful demonstrations of significantly reduced AD-like cognitive symptoms in multiple animal models through enhancing the proteasome's activity. The team developed two novel lead compounds inspired by fragments of a natural proteasome-activating protein. Their peptide-based drug leads are non-toxic, do not cause harmful immune response in animals and easily penetrate the blood-brain barrier. The compounds are reasonably stable, but the team seeks compounds that are more efficient, easier to synthesize and easier to administer to patients. Therefore, the team proposes to develop and test small molecule drug candidates based on their current leads. The team proposes to: (1) Design peptide like molecules by taking advantage of our knowledge about interactions of the current leads with the proteasome. The new compounds will be fast-assessed with purified proteasome and cultured model neurons. (2) Test performance of the most promising small molecules in mouse model of AD with the expected outcome of preparing of a lead compound with excellent drug-like properties and significant protection from AD-like pathology in mice. Future studies beyond the scope of this project will include developing formulation options and preparing an investigational new drug application.

Myron Ignatius, PhD, assistant professor in the Department of Molecular Medicine with a joint appointment at the Greehey Children's Cancer Research Institute.

Project title:Targeting SNAI2 resistance mechanisms in pediatric RAS mutant rhabdomyosarcomas

Description: Rhabdomyosarcoma is a childhood cancer of the muscle. Disease relapse is a major challenge, with less than 40% of patients surviving upon relapse. Therapy for this disease has not changed in the last 20 years and includes surgery to eliminate bulk tumor, radiation-therapy using ionizing radiation and chemotherapy to kill tumor cells. There are no approved targeted therapies and increasing radiation or chemotherapy regimens do not provide any further benefit. Ignatius' research has identified SNAI2 as a major driver of resistance to radiation therapy and showed that SNAI2 protects cells from cell death. In this project, the research team will test whether eliminating SNAI2 can improve outcomes in children with relapse rhabdomyosarcoma. Apoptosis is a critical cell-death pathway in cells and resistance to apoptosis or cell killing, can lead to cancer and the inability of cells to die post therapy. Increasing apoptosis remains a central therapeutic approach in eliminating tumors. SNAI2 is a transcription repressor that binds to the DNA of the critical gene BIM, which is important for cell killing, switching off its expression and protecting cells from radiation exposure. Accordingly, Ignatius' team showed that eliminating SNAI2 rendered cells sensitive to radiation. Proteins like SNAI2 are not easy to target in the clinic, however the team showed that inhibiting the RAS/MEK signaling pathway can also result in the loss of SNAI2 protein. Thus, using a MEK inhibitor with radiation results in the complete loss of tumor. This is a significant finding, but unfortunately the tumors come back two to four weeks later. The project proposes to seek the mechanistic basis for relapse. The team discovered that when SNAI2 is lost and BIM is induced, another protein BCL-xL is also induced. BCL-xL is an anti-apoptotic protein that binds to BIM to prevent it from activating cell death in cells. They also discovered that SNAI2 turns off BCL-xL gene expression in addition to BIM. They hypothesize that eliminating BCL-xL in SNAI2 deficient cells would enable BIM mediated cell killing in SNAI2 ablated or MEK inhibitor treated cells. They will test their hypothesis in several ways including: (1) Determining if SNAI2 and not any other protein is the basis for combining MEK inhibitor with a BCL-xL inhibitor. (2) Determining how SNAI2 binds DNA and switches off BCL-xL expression. While BCL-xL inhibitors are promising, patients cannot tolerate this inhibitor due to a side effects due loss of blood platelets, which are essential for blood clotting. Collaborators have found a novel way to prevent loss of BCL-xL in platelets while maximizing its elimination in tumor cells. The team will test if combining MEK inhibitor, SNAI2 ablation, with a BCL-xL tumor specific inhibitor (PROTAC) will eliminate and prevent resistance to apoptosis in RAS mutant rhabdomyosarcomas. If successful, the study will provide the necessary data to test this combination along with radiation in children with apoptosis resistant rhabdomyosarcoma tumors.

Margaret Flanagan, PhD, professor in the Department of Pathology with a joint appointment at the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases.

Project title:Investigating tri-glial dysfunction and TDP43 in Alzheimer's Disease progression

Description: Alzheimer's disease (AD) is a substantial cause of death and disability in the United States and worldwide. In addition to the plaques and tangles that are classically observed in the AD brain, there are other types of coexisting brain lesions that contribute to the development of AD dementia. One such lesion, pathologic transactive response DNA-binding protein 43 (TDP43), is a protein that has been strongly associated with memory impairment. Pathologic TDP43 is defined as the abnormal movement of the TDP43 protein from its normal location within a cell's nucleus into the cytoplasm. The TDP43 protein is normally present inside the nucleus of neurons and other cell-types in the human brain. When the TDP43 protein relocates from its normal nuclear location into the cytoplasm of cells, abnormal inflammation occurs in the brain and memory problems develop. Flanagan's project proposes to delineate mechanisms behind pathologic TDP43's effects on inflammatory activation in different types of brain cells and determine how these changes impact memory. Her research team will utilize Nun Study and Honolulu Asia Aging Study autopsy brain samples from study groups stratified to have matching AD pathology levels and differing clinical and pathologic TDP43 status with exclusion of co-existing brain lesions. The proposal has two aims: (1) To identify cellular proteomic signatures in autopsy brains associated with TDP43 and memory impairment. (2) To determine the impact of pathologic TDP43 on the known AD transcriptome using digital spatial profiling. Results will inform on tri-glial (astrocyte, microglia, oligodendrocyte) cellular dysfunction and non-autonomous neuronal death mediated by pathologic TDP43. Addressing these critical gaps will also establish the necessary foundation for the discovery of new effective therapeutic interventions in AD.

Feng-Chun Yang, MD, PhD, tenured professor in the Department of Cell Systems and Anatomy and the A.B. Alexander Distinguished Chair in Cancer Research.

Project title:Exploration of a novel therapeutic strategy for pediatric T-acute lymphoblastic leukemia

Description: The most common pediatric malignancy is acute lymphoblastic leukemia (ALL), of which T-cell ALL (T-ALL) comprises about 15% of cases. Pediatric T-ALL is an aggressive malignancy that has historically been associated with a very poor prognosis. Therefore, there is an unmet need to develop novel and more effective T-ALL therapies, which requires a deeper understanding of the pathophysiology of T-ALL and the identification of novel and effective molecular targets. Advanced genome sequencing technology has allowed the identification of the most frequent gene mutations in pediatric T-ALL, which includes NOTCH1 (~20%), FBXW7 (~20%) and PHF6 (~15%). The mechanisms by which PHF6 mutations lead to leukemic transformation of T-lymphoid precursors are completely unknown. In the past several years, utilizing several newly generated PHF6 mouse models, Yang and her team discovered that it is via gain-of-function by the protein product resulting from the mutated PHF6 gene, the mutated PHF6 gene causes abnormalities in blood precursor cells and results in excessive neoplastic cell growth by activating oncogenic genes and inhibiting tumor suppressor genes. Therefore, the neogenic truncated PHF6 protein product and its gained oncogenic pathways are ideal targets to develop tailored and effective therapeutics for pediatric T-ALL harboring a PHF6 mutation. In this project, the team will identify the gained pathways of the neogenic PHF6 truncation protein product that are critical for T-ALL leukemic transformation, and rationally target the truncated PHF6 proteins and its gained oncogenic pathways to eradicate PHF6-mutated T-ALL in mouse models. Since PHF6 mutations also occur frequently in adult blood cancers and a pediatric hereditary disorder (Borjeson-Forssman-Lehmann syndrome), success of the proposed studies will have profound impact on the development of therapeutics far beyond the pediatric T-ALL. Yang, in collaboration with colleagues, has established unique PHF6 mouse models and identified the gain-of-function by PHF6 mutations as the main culprit for leukemic transformation. Success of the proposed studies will pave the way for the translation of these findings into therapies for pediatric T-ALL and many other diseases with PHF6 mutation.

Manjeet Rao, PhD, professor in the Department of Cell Systems and Anatomy.

Project title: Targeting metabolic vulnerabilities in pediatric brain tumor

Description: Medulloblastoma is a fast-growing tumor of primary central nervous system (CNS) with a dismal five-year survival rate and a high risk of recurrence within two years of treatment. Medulloblastoma stem cells are the main culprits that are responsible for drug resistance and recurrence. Patients who do survive have substantially reduced quality of life due to the high toxicity associated with radiation and chemotherapy. Therefore, identification of new drivers and pathways that support medulloblastoma stem cell growth is critical to develop potent therapeutic drugs that can eradicate medulloblastoma without inducing any neurotoxicity is urgently needed. Rao and his team discovered a novel protein (SKP2) that can sustain medulloblastoma stem cells as well as make medulloblastoma resistant to radiation and chemotherapy. Their results reveal that inhibiting the expression or activity of SKP2 can block the growth of medulloblastoma and make them sensitive to low dose of radiation. Their research further showed that SKP2 uses glutamine and arginine metabolic pathways to support medulloblastoma stem cell. The successful completion of this study will set the stage for a new paradigm of treating medulloblastoma using SKP2 inhibitor or glutaminase inhibitor CB-839, which is currently in clinical trial for adult brain tumor, and arginine inhibition using pegylated arginine deaminase (ADI-PEG20), which is in clinical trial for adult cancers, alone or in combination with radiation in medulloblastoma patients without any delay.

Shaun Olsen, PhD, associate professor in the Department of Biochemistry and Structural Biology.

Project title: Structure and function of RAD51 paralogs in homologous recombination

Description: The stability of the human genome is of paramount importance to life. DNA is under constant threat from damage resulting from both internal and external sources. The ability to identify and repair damaged DNA is of extreme importance as failure to do so can lead to genome instability and cancer. One of the most toxic forms of DNA damage occurs when both strands of double stranded DNA are broken at a similar place on a chromosome, as it is difficult to accurately repair the DNA break. The way that cells manage to accurately repair double stranded DNA breaks is by taking advantage of the fact that humans have two copies of their chromosomes. A DNA repair pathway called homologous recombination (HR) manages to use the undamaged, "good" copy of DNA as a reference for repairing the region of double stranded DNA breaks in the "bad" copy of the DNA. One of the key players in HR is a protein called RAD51, which binds to DNA at the double stranded break and then conducts a search of DNA in the cell to find the corresponding undamaged region on the good copy of the DNA sequence. Once homology is identified, RAD51 then facilitates repair in what is generally considered to be an error-free manner. RAD51 has been very well studied for nearly sixty years and many details are known about how it functions in the repair of double stranded DNA breaks. With that said, RAD51 cannot function by itself in this process and relies on a number of other proteins called mediators that are required for its ability to repair double stranded DNA breaks though HR. Among these many mediators are a group of proteins that are structurally related to RAD51 but come from different genes and fulfill different functions. These related proteins are referred to as RAD51 paralogs. The goal of this project is to learn how the RAD51 paralogs promote RAD51-mediated repair of double stranded DNA breaks by learning what the paralogs look like in three dimensions and thoroughly characterizing how these proteins work both in a test tube and in human cells. Learning what these paralogs look like and how they work will not only expand theoretical knowledge of RAD51-dependent HR, but will also provide new platforms for understanding how cancers develop and behave, as well as for the development of cancer therapeutics.

Daohong Zhou, MD, professor with tenure in the Department of Biochemistry and Structural Biology, associate director for drug development at the Mays Cancer Center and director of the Center for Innovative Drug Discovery.

Project title: Develop an improved second-line therapy for relapsed and refractory pancreatic cancer

Description: Pancreatic cancer (PC) is one of the most highly aggressive cancers in humans with a five-year survival rate of less than 5%. This is primarily attributed to the lack of early detection and a high resistance of PC to treatment. An increasing body of evidence demonstrates that the increased expression of a protein called BCL-XL plays an important role in the resistance of PC to chemotherapy and radiation. Previous studies have shown that inhibition of this protein with an inhibitor called navitoclax, or ABT263, can increase the sensitivity of PC cells to cancer treatments. However, BCL-XL is also required for the survival of platelets, which are important for blood clotting to stop or prevent bleeding. Therefore, navitoclax cannot be used to treat PC patients because it causes severe thrombocytopenia or platelet reduction and bleeding. We have developed a new strategy to selectively degrade BCL-XL in tumor cells but not in platelets, resulting in the generation of DT2216, which can target BCL-XL to an enzyme called E3 ligase that is minimally expressed in platelets but highly expressed in various tumor cells to mediate BCL-XL degradation. Compared with navitoclax, DT2216 exhibited improved antitumor activities but reduced platelet toxicity in vitro. DT2216 in combination with other chemotherapeutic agents effectively inhibited tumor growth without causing thrombocytopenia in a number of animal models engrafted with human tumors including PC. Therefore, DT2216 was approved by the FDA as an investigational new drug, and has been in phase 1 clinical studies since 2021 at the Mays Cancer Center and two other sites. The preliminary analyses of the phase 1 studies showed that DT2216 can effectively degrade BCL-XL in blood cells without causing significant reduction of blood platelets and any other toxicities at a dose level that can be recommended for further clinical studies in patients with various relapsed and refractory malignancies. Several patients showed partial response or stable disease after DT2216 treatment. Without the treatment, patients succumb to their diseases rapidly. One of the PC patients who failed to respond to three previous lines of chemotherapy showed a 27.3% reduction of her primary tumor after treatment with DT2216. These findings are very encouraging considering that DT2216 was designed to be combined with chemotherapy to kill tumor cells. Based on these findings, this project proposes to conduct laboratory studies to evaluate the therapeutic efficacy and toxicity of the combination of DT2216 with a commonly used chemotherapy regimen in the clinic in various PC cell lines in cell culture and in patient-derived PC tumor models. Zhou and the research team expects that the combination therapies will have improved therapeutic efficacy without increased toxicity compared to individual treatments against PC. The findings from these studies will allow for the development of a better second-line therapy for relapsed and refractory PC.

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