1. < Digestive Diseases

Faculty in the Department of Medicine at UCLA (DoM) are at the forefront of leading innovative research studies that inform the prevention, detection and treatment of medical conditions that impact countless lives. Each week, I receive a report detailing our faculty’s research publications and commentaries in academic journals which disseminate our knowledge and understanding about medicine and science with peers and colleagues around the world. I invite you to view our collection of faculty publications which are updated weekly on our DoM Connect Blog.

Let me share with you a sample of recent groundbreaking research taking place in our department and invited commentaries on other landmark studies. This snapshot is just a partial representation of our department’s total research output. Thanks to each faculty member who shared additional perspective on the impact of their publications.

Matthew Freeby, MD & Maria Han, MD, MS, “Barriers to Implementation of Teleretinal Diabetic Retinopathy Screening Programs Across the University of California,” in Telemedicine and E-Health

"Diabetic retinopathy (DR) is a leading cause of preventable blindness among adults in the United States.Timely retinopathy screening and treatment may prevent blindness. Despite screening recommendations, real-world completion rates remain low due to limited health care access, transportation, cost, education on screening importance, and anxiety about diabetes complications. To address these barriers, several institutions have adopted teleretinal screening programs, but there continues to be significant issues regarding sustainability.

In this publication, researchers across UC institutions surveyed patients and providers to better understand the specific barriers to implementation of diabetic teleretinal screening programs, as well as artificial intelligence integration. Representatives from UCLA, UCSD, UCSF, UCI and UCD assessed program initiation, clinic staff involvement, screening image quality, image turnaround time, and billing codes. At the time of the study, the UC campuses had screened between 250 and 2100 patients per campus. Barriers to successful implementation and sustainability included patient education, resource availability, and support infrastructure. Cost and integration into existing technology infrastructures were identified as barriers to AI integration in DR screening.

The UCLA effort has been led by Drs. Maria Han and Matt Freeby, both co-authors on the publication; the team is now spearheading an effort to improve access to retinal screening by expanding our teleretinal imaging program. Gaining an understanding of the barriers of teleretinal screening through this research has guided the team in its pursuit of adding more cameras into primary care and endocrine clinics throughout the health system with the aim for sustainable, long-term use. In time, the aim is to increase diabetic screening via improved access for patients with diabetes across the health system."

Utibe Essien, MD, MPH, “Association of Prescription Co-payment with Adherence to Glucagon-Like Peptide-1 Receptor Agonist and Sodium-Glucose Contransporter-2 Inhibitor Therapies in Patients with Heart Failure and Diabetes," in JAMA Network Open

Brandon Nadres, BSc, Milica Momcilovic, MD, PhD, David B. Shackelford, PhD, Aaron Lisberg, MD, “An Unexpected Partnership: Histone Deacetylase 6 and Glutaminase Inhibition Provide an Opportunity to Overcome Resistance in KRAS and LKB1 Co-mutant Lung Tumors,” in Journal of Thoracic Oncology

“This editorial, a collaboration between The Lisberg and Shackelford Labs, contextualizes a recent study published by Zhang et al. in the Journal of Thoracic Oncology (JTO) that investigated a novel therapeutic strategy for targeting metabolic vulnerabilities in KRAS/LKB1 co-mutant non-small cell lung cancer (NSCLC), a NSCLC subtype that is a focus of our labs and are highly resistant to standard chemo-immunotherapy approaches. Specifically, the use of histone deacetylase 6 (HDAC6) and glutaminase inhibition was evaluated in these tumors, leading to disruption of important metabolic pathways involved in energy production and tumor growth. This combinatorial approach was effective in both KRAS/LKB1 mutant NSCLC cell culture and mouse models, providing the groundwork for a new therapeutic approach in the management of this difficult to treat subset of NSCLC.

Patients with KRAS/LKB1 mutant NSCLC experience significantly less benefit from currently approved treatment approaches and, as such, have poor clinical outcomes. That said, no specific therapies have been approved for the management of this aggressive disease subtype. Therefore, the identification of metabolically targeted treatment approaches that are effective for patients with KRAS/LKB1 mutant NSCLC is of critical importance to the lung cancer field.

Although the combined inhibition of glutaminase and HDAC6 showed promise in the JTO manuscript by Zhang et al, the prior failure of the KEAPSAKE clinical trial, which similarly hypothesized that targeting glutaminolysis and oxidative stress via glutaminase inhibition would be beneficial for patients with KEAP1/NRF2 mutations, emphasizes the importance of (a) precise patient stratification for treatments that target oxidative stress and metabolism, (b) targeting multiple metabolic nodes, and (c) identifying the metabolic nodes most vulnerable to perturbation. As such, additional pre-clinical work remains to be done before this therapeutic combination is evaluated in patients.”

Nuria Martinez-Lopez, PhD & Rajat Singh, MD, MBBS, “mTORC2–NDRG1–CDC42 axis couples fasting to mitochondrial fission,” in Nature Cell Biology

“In our publication in Nature Cell Biology, we show that fasting unexpectedly stimulates a signaling pathway namely, mTORC2 in the liver. This pathway is typically known to be activated by insulin and feeding. However, activation of mTORC2 supports mitochondrial function and health during fasting, including mitochondrial dynamics and respiration. Using complementary approaches, we identify a new pathway downstream of mTORC2, the NDRG1-CDC42 cascade, which engages with mitochondria to support its health and wellbeing. Indeed, inactivating mTORC2 or NDRG1 or Cdc42, each leads to marked disruption of mitochondrial health and function and the inability of the liver to effectively eliminate its lipid stores. We have therefore identified a new role for mTORC2 in coupling nutrient sensing to control of mitochondrial function in liver.

Mitochondria are critical for organismal survival because of their fundamental role in generation of energy. As we age, regulation of mitochondrial shape, size, dynamics, and respiration decline, which in turn leads to several age-related diseases. It is therefore critical to understand how mitochondria adapt to changes in fasting and feeding, such that we can develop new therapies to maintain mitochondrial function and wellbeing.

Unpublished data from our lab also suggests that many of our observations in this Nature Cell Biology paper are suppressed with age and obesity. It is therefore plausible that strategies sustaining mTORC2 activity will prevent age-related decline in bodily functions. With the likelihood of obtaining new funding on this topic, we will be able to continue our work to understand how age-related changes in mTORC2 function causes human fatty liver disease.”

Diana C. Marquez-Garban, MD, Mario Morales Martinez, PhD, Richard J. Pietras, MD, PhD, “Estradiol Induces Neutrophil Expansion to Promote TSC-Null Tumor Progression,” in Endocrinology

"Our publication was an invited commentary requested by the editor of Endocrinology to provide a brief overview of a recent article published in Endocrinology by Minor et al. entitled “Estradiol Augments Tumor-Induced Neutrophil Production to Promote Tumor Cell Actions in Lymphangioleiomyomatosis Models.” Minor and colleagues reported that estradiol stimulates growth of lymphangioleiomyomatosis (LAM) tumors in part by promoting myelopoiesis (bone marrow cell expansion) and aberrant neutrophil expansion in preclinical murine models. The estradiol-induced lung colonization of such tuberous sclerosis (TSC)-null tumors is dependent on neutrophils, with mechanisms based on increased neutrophil progenitors and promotion of inflammatory cytokines and chemokines. In addition, transcriptomic data from LAM patients affirm the presence of tumor-activated neutrophils that may play a role in promoting TSC-null tumor growth.

Our commentary was solicited due to our previous work entitled “Antiestrogens in combination with immune checkpoint inhibitors in breast cancer immunotherapy.” As in the Minor et al. publication, our research focused on developing new targeted therapies for cancer treatment. About 70% of breast cancers have estrogen receptors and respond to estrogens. Antiestrogen therapies are very effective at reducing tumor recurrence and improving overall survival of breast cancer patients. However, about 50% of women who die with breast cancer have developed resistance to these hormonal treatments. Our work provided evidence that specific exoimmune cell populations present in the breast tumor microenvironment (TME) express estrogen receptors and respond to antiestrogen therapy. In collaboration with Dr. Michael Jung in Chemistry, we have developed new estrogen receptor down-regulators (SERDs) that act directly on estrogen receptor-positive tumors to inhibit tumor growth but also indirectly on the immune TME to reduce aberrant myelopoiesis and to increase tumor-infiltrating lymphocytes (TILs) to overcome breast tumor immune evasion. This estrogen-dependent process appears to also occur in LAM tumorigenesis as reported by Minor et al. 

Further research on interactions between hormonal factors such as estrogens and the immune system are urgently needed to develop new treatment options for patients who stop responding to current therapies. Our new orally-bioavailable SERD compounds have been demonstrated to be effective in preclinical models of treatment-resistant breast cancer not only by direct inhibition of tumor growth but also by targeting immune cell subpopulations in the TME to amplify the anti-tumor response. The potential application of such SERDs in the future management of breast and other estrogen dependent malignancies such as LAM tumors remains to be investigated going forward."

Kevin Qian, MD, PhD Awarded the William N. Valentine Award for Excellence in Internal Medicine

Even as we highlight the scholarship of our faculty, I am very pleased to spotlight and celebrate the work of our trainees who are walking in their footsteps and following close behind. At last week’s DoM Grand Rounds, the DoM Education Team honored Kevin Qian, MD, PhD with the William N. Valentine Award for Excellence in Internal Medicine. Dr. Valentine was the second chair of medicine from 1963-1971. Dr. Valentine was internationally acclaimed for his seminal research that describes the fundamentals of red blood cell physiology, particularly his work in describing the role of changes in metabolic enzyme function that could contribute to disorders such as hemolytic anemia. We are thrilled to present this award to Dr. Qian, who is a member of our physician scientist training residency program, now integrally linked with the STAR Program. The award recognizes his superior performance as a scholar in internal medicine and outstanding scholarly achievements throughout medical school. As an endocrinologist, I am also pleased that Kevin has decided to pursue a career in endocrinology.

As an MD PhD graduate student at UCLA, Kevin published a landmark paper in the journal Natureearlier this year describing the way in which fat cells (adipocytes) store lipids in droplets and ultimately burn these lipids in ways that can promote weight loss.

The future of medicine is bright with trainees like Dr. Qian who are building upon our department’s history of innovation in scholarly research and patient care. Congratulations Kevin!

Dale

P.S.

A little over a week ago, I was briefly in Jamaica to speak at the 75th Anniversary Celebrations of my Medical School at the University of the West Indies. Of course, I seized the opportunity to bring back to LA, a box of the quintessential Jamaican street food. You can buy 1 dozen patties from various outlets. But my mother directed me to this one, because when you order 1 dozen they actually give you 13!

---