Year 4. February 3. Our Research Will Continue.
A core strength of our department is our unwavering commitment to advancing the field of medicine through innovative research that transforms how we treat disease and promote health and wellbeing for our communities. We are dedicated to accelerating the growth and impact of our work, driving innovation and discovery. However, last week we faced uncertainty about federal funding for our projects due to a funding freeze. Although the funding freeze has for now been rescinded, I understand that many of you may be feeling confused, overwhelmed and frustrated; I share your concerns.
While it is possible that we may face similar situations in the future, I want to assure you that our department will be working closely with UCLA, the David Geffen School of Medicine at UCLA, the entire UC system and other experts to obtain accurate information about how these orders could impact our work. We will share that information with you as facts are confirmed.
Those of you who are faculty, post-doctoral scholars and graduate students received an email notice on Wednesday, January 29 and Sunday, February 2 from Vice Chancellor Wakimoto detailing UCLA’s recommendations on maintaining the continuity of your research projects in this uncertain time. While you should keep an eye out for communications from your funding agency, UCLA’s Office of Research Administration and the Office of the Vice Chancellor for Research and Creative Activities Office, you should manage your funding and expenses as planned unless you are instructed otherwise, including timely submission of progress reports and other reporting requirements. If you receive any stop-work orders, terminations or suspension notification from funding agencies related to the Executive Orders, please forward them to awards@research.ucla.edu. You may find the latest announcement from the UCLA Office of the Vice Chancellor for Research and Creative Activities by clicking here.
Our research community is essential to the wellbeing of our patients and the success of our department. We will work together to minimize disruption to the critical work that we are leading. The UCLA Department of Medicine (DoM) is actively focusing on strategies to increase the resiliency of our research enterprise, and we will be communicating further in multiple forums in the coming weeks.
Let me now turn the spotlight to a few of our many outstanding investigators whose recent research accomplishments exemplify our commitment to lead in innovation, transform care, and advance health for all.
Lloyd Harvey, MD, PhD Publishes Major PAH Discovery in Science
Recently I was delighted to learn of a major accomplishment by one of our trainees. Second-year resident Lloyd Harvey, MD, PhD, a member of the STAR-PSTP program, on Jan. 24 published a groundbreaking discovery in Science that will have a major impact on our understanding of pulmonary arterial hypertension (PAH), a deadly disease with few treatment options. It also illuminates the effects of single nucleotide polymorphisms (SNPs) and shows how we can demonstrate their physiological function using multi-omics, a biological analysis technique that utilizes high-throughput data collection modalities like genomics, metabolomics, transcriptomics, and others to obtain a holistic picture on how a cell or organism functions.
“One of the great struggles in the post-genomic era has been the inability to take a statistical association with a SNP and some sort of outcome and actually prove that it has biological functionality,” Dr. Harvey explained. “That’s what this study does.”
The research outlined in the publication addressed two lines of inquiry. The first centered on the molecular underpinnings of PAH and whether the researchers could develop an effective therapeutic — a challenge they accomplished successfully in rat models. After using rodent models and patient data to confirm that the inactivity of the gene NCOA7 is correlated with PAH pathologies and symptom severity through the disruption of lysosomal function and resultant production of proinflammatory oxysterols and bile acids, the researchers developed a drug, 958ami that activates NCOA7 to restore lysosomal function and reverses PAH in rats.
In another set of parallel experiments, the researchers found in a metabolomic cohort of nearly 3,000 PAH patients a signature of unidentified metabolites that were associated with mortality. Additional structural analysis found that these metabolites were oxysterols and bile acids — the same proinflammatory molecules produced with NCOA7 inactivity.
Further leveraging population-level cohorts of PAH patients, the researchers examined genetic variants within NCOA7 to see if any had clinical prognostic utility. Specifically, substitution to a G nucleotide from the wildtype C allele was associated with significant improvement in six-minute walk test and mortality. To confirm biological functionality, they performed CRISPR/Cas9-SNP editing to produce isogenic inducible pluripotent stem cells differentiated into endothelial cells. Cells harboring the G allele of the SNP rs11154337 had increased NCOA7 activity, preserved lysosomal function, decreased levels of oxysterol and bile acid production, and dampened endothelial inflammation. These findings provided a possible molecular explanation as to why patients carrying the G allele have better clinical outcomes.
Dr. Harvey noted that these findings are particularly relevant given the deluge of data that continues to be produced across various modalities.
“In this new era of high throughput data acquisition, we have an excess of information at various biological layers within a disease process, but we have struggled to harmonize these large datasets in truly understanding disease,” Dr. Harvey said. “In this case, we provide a translational roadmap on how in vitro and in vivo mechanisms can inform population-level genomics and metabolomics datasets and vice versa, while simultaneously using in silico modeling to create a novel therapeutic agent.”
Dr. Harvey and his team believe that NCOA7 is implicated in vascular diseases more broadly, as well as diseases of immune dysregulation. They have several studies in progress that examine the role of the gene in COVID-19, for example — studies that also offer evidence that 958ami reverses COVID-19 mortality in mice. Furthermore, mouse models of sepsis and ischemic stroke suggest that a similar mechanism is playing out in those conditions as well.
Please join me in congratulating Dr. Harvey on an outstanding publication! I am pleased that Lloyd will continue his career at UCLA as a cardiology fellow. We have high hopes that this landmark study will be the first of many research advances that Lloyd will make as he establishes his independent career when his training is over!
Carlos Oronce, MD, PhD, MPH Disaggregates Data to Highlight Disparities Among Asian American Subgroups in Medicine
As many of you know, one of our core missions in the DoM is to Advance Health for All. A vital strategy toward this objective is ensuring that physicians are as diverse as the communities they serve, as there is abundant evidence that patients have better outcomes when they receive culturally competent care. Yet when it comes to Asian Americans, there is a major obstacle: Despite the fact that they originate from over 40 different countries of origin and speak more than 50 different languages, there is a strong misconception that they are a monolith and are therefore overrepresented in medicine.
In fact, multiple Asian American subgroups are underrepresented, as Carlos Oronce, MD, PhD, MPH recently demonstrated in an insightful study published Nov. 15 in JAMA Network Open. By analyzing AAMC data from hundreds of thousands of allopathic medical school applicants, matriculants, residents and faculty who identified as Asian American, Dr. Oronce showed that Filipino Americans, Cambodian Americans and Laotian Americans are marginalized at every stage of the physician workforce pipeline.
“The question of Asian American subgroup representation in medicine hadn’t really been asked before in a comprehensive way,” Dr. Oronce said. The “model minority” myth — the notion that all Asian Americans are wealthy, highly educated and hold well-paying jobs in medicine and business— has created a blind spot that erases the challenges that many subgroups face. In fact, as of 2018, wealth inequality between Asian American populations was rising faster than for any other ethnic group.
Those socioeconomic disparities translate to representation disparities in medicine, a field that is notoriously capital-intensive for prospective entrants. For example, for all subspecialties, the “representation quotient” for Laotian and Cambodian medical residents hovered near zero, compared to five or more for residents of Pakistani or Taiwanese descent. These groups also have higher rates of poverty and lower incomes compared to other Asian American populations, along with possible trauma if they or their family members were among the many in those groups to come to the U.S. as refugees. A lack of physicians from their backgrounds means fewer mentors for the next generation, as well.
“These are unique aspects of their experience that aren’t really addressed in the medical school setting,” Dr. Oronce explained.
For Filipinos, economic and cultural factors, the legacy of American colonialism and racism may play a role in why relatively few of them become physicians, despite being represented proportionally among medical school applicants and having a higher average income than many other Asian American subgroups. Many Filipinos are encouraged by their families to become nurses rather than doctors, a historical remnant of the nursing schools the U.S. set up in the Philippines to address a workforce shortage. Qualitative data suggests that Filipino American parents encourage their children to go into nursing or other allied health professions rather than to become physicians in order to attain a high-paying occupation sooner while meeting parental expectations of starting a family.
These disparities have significant implications for patients as well as for medical education. Patients from Laotian, Cambodian and Filipino communities are in great need of more culturally- and linguistically concordant physicians. To address this shortage, medical schools should think more broadly about what underrepresentation means, and those who can collect self-reported data should offer faculty and matriculants more choices besides “Asian” to disaggregate their data and get a real sense of who makes up their student bodies.
“Data aggregation reinforces Asian Americans as a monolith and, if we really think about the history of Asian Americans, we see a mechanism of structural racism because it erases the histories and experiences of students who are Laotian, Cambodian and Filipino, for example,” Dr. Oronce said. “Data disaggregation is really a way to advance racial justice within medical education.”
In addition, support for mentoring programs like First-Gen @ UCLA DGSOM would also go a long way toward strengthening the pipeline of underrepresented Asian American subgroups in medicine. Such initiatives help students from marginalized backgrounds learn the “hidden curriculum” of cultural and social norms that underlie the profession.
“We need to make sure that students feel like they belong when they come into the medical school environment and that they aren’t afraid to ask for help,” Dr. Oronce said. “We should be offering ways to help them on this journey, because it’s challenging.”
Please join me on congratulating Dr. Oronce on this impressive and important piece of scholarship. His work represents an important step towards addressing important disparities in medical workforce development, an imperative that we should not lose sight of.
VA Selected As New Site for VABIO APOLLO Program to Advance Precision Medicine
The DoM’s longstanding partnership with Veterans Affairs of Greater Los Angeles (GLA-VA), continues to be an engine that generates significant progress in education, training and scientific advances. This will be further amplified as we become a new site for the VABIO Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) program, a joint initiative between the Department of Veterans Affairs, the National Cancer Institute and the Department of Defense. As an APOLLO site, VA cancer patient biospecimens will be sent to a central biobank repository for studies using multi-omic techniques assessing the genetic, protein, microbial and metabolic composition of tumors. This will enable advances in translational research leading to more effective targeted cancer therapies. Our investigators will have access to data not only from GLA-VA patients but also from the entire APOLLO network.
“The goal of VABIO APOLLO is to have a nationwide biobank large enough to answer some of the key questions about how cancer develops and how best to apply personalized medical care. This will be facilitated through the use of the latest multi-omic technologies,” said Steven Dubinett, MD, Professor of Medicine and DGSOM dean, who leads the GLA VABIO APOLLO together with VA Chief of Surgical Oncology and Professor of Surgery James S. Tomlinson, MD, PhD. “This program will help us with diagnostic issues and, as we move forward with artificial intelligence and other modern tools, enable us to make predictions about clinical outcomes.”
Drs. Dubinett and Tomlinson’s extensive experience in biobanking was one of the primary reasons for the GLA-VA’s acceptance into the program. Dr. Dubinett who has developed biobanking for the NCI Early Detection Research Program, the Specialized Program of Research Excellence in Lung Cancer and, in leading the CTSI, has collaborated with the UCLA Institute for Precision Health to launch the ATLAS Community Health Initiative, which is enrolling more than 150,000 patients into the UCLA Precision Health Biobank.
“We can do studies at UCLA, but we can do much more with our colleagues in national collaborations. The opportunity to have a curated data repository with human tissues and biospecimens allows us to more fully understand cancer heterogeneity in order to effectively develop precision medicine treatment,” Dr. Dubinett said.
The program will use existing local facilities to collect and process samples and will employ additional clinical coordinators and staff members to collect biospecimens in keeping with informed consent. This will make it possible for the many VA patients who undergo surgery each year to participate in the program.
“In our anticipated best-case scenario, the data collected from the program could even lead to advances that make it possible to stop cancer before it even starts. We’ll be able to get to the point where we’re looking not only at cancer but cancer risk. Understanding the heterogeneity of risk and its underlying mechanisms will enable the treatment of risk and promotion of health,” he said.
In Study Led by Aditya Bardia, MD, MPH, Antibody Drug Conjugate Bests Chemo for Metastatic Breast Cancer
Next I am excited to share with you new research led by Aditya Bardia, MD, MPH, director of translational research integration at Jonsson Comprehensive Cancer Center. His team led a large multi-center trial that involved 866 patients diagnosed with hormone receptor-positive (HR+), HER2-low or HER-2 ultralow metastatic breast cancer who had unsuccessfully been treated with least one endocrine therapy but had not previously been treated with chemotherapy. They were randomized to receive either an antibody-drug conjugate (ADC) called trastuzumab deruxtecan (T-DXd) or chemotherapy.
In an article published Dec. 5 in the New England Journal of Medicine, Dr. Bardia’s team demonstrated that the drug extended progression-free survival to 13.2 months, compared to 8.1 months for individuals in the chemotherapy arm. Additional results presented at the San Antonio Breast Cancer Symposium showed that T-DXd had activity in all subgroups, including patients whose cancer had progressed in less than six months on first-line endocrine therapy. The overall response rate was higher with T-DXd over chemotherapy, with 57.3% of patients responding to T-DXd versus 31.2% of patients responding to chemo.
The results highlight T-DXd as a new treatment for patients with endocrine-resistant metastatic breast cancer. Apart from CDK 4/6 inhibitors, T-DXd is the only drug to demonstrate progression-free survival for more than 12 months.
“This clinically meaningful benefit establishes T-DXd as a potential standard of care in patients in this setting,” Dr. Bardia said. Moving forward, his team will conduct additional research to develop T-DXd in other indications, develop better predictive biomarkers and understand mechanisms of therapeutic resistance to further improve outcomes for patients with breast cancer.
I would like to note that trastuzumab, the agent that makes up part of T-DXd, is a groundbreaking drug developed in the early 1980s by UCLA oncologist Dennis Slamon, MD, Chief of the Division of Hematology and Oncology in the DoM, and director of clinical/translational research and the Revlon/UCLA Women’s Cancer Research Program at JCCC. It is immensely gratifying to see the impact of these seminal discoveries continue to evolve here at UCLA!
DoM Researchers Make Up 1/3 of UCLA Faculty Among World’s Top-Cited Scholars
As you can see from these examples of scholastic and research excellence in this week’s newsletter, the talent of our research faculty in the DoM knows no bounds. A recent analysis by Clarivate, an international data analytics firm, confirms this: Thirteen DoM faculty members are among the world’s most influential scholars, ranking in the top 1% for papers cited in their fields over the past ten years. Of the 39 UCLA faculty who hold this designation, a full third of them are from the department of medicine.
“The strong representation of DoM faculty on this highly cited researcher list underscores the impact of the work being done at UCLA. When a researcher’s work is cited by others, whether it be a primary research result from the lab, the outcome of a clinical trial or a new clinical guideline, it shows that others are building off the results of our work,” said Judith Currier, MD, MSc, executive vice chair for research and professor of medicine. “Citation metrics are one of the many ways that we can measure the influence of our work, and it demonstrates how much our research informs both specific scientific areas and the practice of clinical medicine.”
According to Clarivate, researchers who can count themselves as the world’s most influential are one in a thousand. I may be biased, but I would argue that the combination of passion, scientific achievement and dedication to patient care exemplified by the DoM faculty on this list makes them far rarer — perhaps more like one in million! As we continue to nurture the talents of our research faculty in alignment with our strategic plan, their influence on the medical field is will only continue to grow. I hope to see more UCLA investigators join this prestigious group!
Please join me in congratulating those who were recognized on Clarivate’s list and in thanking them for their hard work:
Finally, for the many in our community who observed the Lunar or Chinese New Year this past week, Happy New Year!
Dale
P.S.
P.S. My mom turned 90 this weekend. Her children, their partners and some of her grandchildren all gathered in Kingston to celebrate this milestone with her. She was very pleased!
Pictured are my mother with her 5 children, and mother with one of her daughters-in-law
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