Stanford ChEM-H solicited proposals from small teams of clinicians and scientists or engineers who are interested in undertaking exploratory studies involving human subjects.
The mission of Stanford ChEM-H is to understand human biology at a molecular level, and to engineer molecules, materials and tools that will impact human health. A key limiting factor for testing molecular hypotheses or evaluating promising new tools in humans is the establishment of productive connections between molecular scientists/engineers with access to innovative tools and practicing clinicians with access to sick or healthy cohorts of human subjects. Together, these scholars can test bold hypotheses in humans, or validate the utility of a new tool in the diagnosis or management of a disease. Five proposals were selected from a competitive pool of applications for one year of funding beginning in March 2019.
"Rapid Target Enrichment from Plasma and Urine for Streamlined and Sensitive Diagnosis of Mycobacterium tuberculosis using Liquid Biopsy"
Laboratory Based Investigator: Juan Santiago, Mechanical Engineering
Clinical Based Investigator: Niaz Banaei, Pathology and Medicine - Infectious Diseases
Tuberculosis (TB), an infection caused by Mycobacterium tuberculosis, remains a challenge to diagnose, especially in younger children who cannot expectorate, HIV-infected patients, and those with TB disease outside the lungs, where invasive sampling is required. To address this need, we developed a simple and inexpensive test called the genome-wide sensitive (GWiS) nucleic acid amplification test (NAAT) to detect Mycobacterium tuberculosis cell-free DNA (cfDNA) in plasma and urine. In preliminary evaluation of GWiS in plasma samples from adult patients with pulmonary and extrapulmonary tuberculosis, and non-TB patient controls, it was shown to have an overall sensitivity of 74% and specificity of 100%. The proposed study aims to comprehensively assess and optimize the test performance of this assay, including application of a novel cfDNA extraction and enrichment system, and to evaluate the optimized assay in children and adults with the eventual aim of development into a point-of-care format.
"Soluble CA-125 in Ovarian Cancer: Functional Implications and Therapeutic Targeting"
Laboratory Based Investigator: Carolyn Bertozzi, Chemistry
Clinical Based Investigator: Oliver Dorigo, Obstetrics & Gynecology - Gynecologic Oncology
Ovarian cancer is a devastating disease with few treatment options available other than cytotoxic chemotherapy and debulking surgery. The serum biomarker CA-125 is routinely used to monitor patient response to therapy in the clinic thanks to its high soluble levels in blood and the correlation of those levels with disease burden. There is mounting evidence that soluble CA-125 is not only a marker of cancer but in fact, functionally promotes tumor progression by binding immune cells all over the body and inhibiting their activity. Efforts to target CA-125 therapeutically have been complicated by its unique structural properties. CA-125 is a member of the mucin family of proteins, which are large proteins that, as a result of heavy modification with sugar residues, are resistant to degradation or blocking. The Bertozzi and Dorigo groups have recently characterized a bacterial mucin-degrading enzyme with the ability to cut human CA-125 into fragments. With the support of Testing Molecular Hypotheses in Human Subjects funding, our groups are using this enzyme to study ovarian cancer patient tissues. We hope to not only better understand how CA-125 suppresses the immune system, but also test the therapeutic potential of our enzyme for the treatment of ovarian cancer.
"Microbiome Biomarkers to Predict CAR-T cell Exhaustion and Therapeutic Efficacy"
Laboratory Based Investigator: Ami Bhatt, Medicine - Hematology, Genetics
Clinical Based Investigator: Andrew Rezvani, Medicine - Blood and Marrow Transplantation
Non-Hodgkin lymphoma accounts for 4% of all cancers in the United States, with diffuse large B-cell lymphoma (DLBCL) comprising the majority of cases. One third of patients with DLBCL will develop relapsed or refractory disease for which prognosis remains extremely poor. Anti-CD19 chimeric antigen receptor (CAR) T cell treatment is an emerging and promising immunotherapy for relapsed/refractory DLBCL, although long-term success is often limited by the lack of a durable CAR T cell response, or so-called “persistence”. CAR T-cell persistence is required for anti-tumor efficacy, however, the progressive repression of cellular effector function within the tumor micro-environment, known as T-cell exhaustion, is a major limiting factor to CAR T cell effectiveness. It is known that the human intestinal microbiome can impact the abundance of anti-inflammatory cytokines, which may in turn affect immunological function generally, and T-cell persistence/exhaustion, specifically. In keeping with this model, the microbiome significantly impacts the efficacy of checkpoint inhibitor therapy through its immunologic effects on the tumor microenvironment. Here, we propose to test the hypothesis that the intestinal microbiome is a biomarker of and may be a mediator of CAR-T cell therapy efficacy by impacting T-cell persistence and activity within the tumor microenvironment.
"Changes in [18F]DASA-23 PET Uptake, a Measure of Pyruvate Kinase M2, from Pre- to Post-therapy in Recurrent Glioblastoma: Effects on Survival"
Laboratory Based Investigator: Sam Gambhir, Radiology
Clinical Based Investigator: Lawrence Recht, Neurology & Neurological Sciences
This clinical trial studies how well the [18F]DASA-23 positron emission tomography (PET) scan works in evaluating pyruvate kinase M2 (PKM2) expression in patients with recurrent glioblastoma. PKM2 regulates brain tumor metabolism, a key factor in glioblastoma growth. [18F]DASA-23 is a radioactive substance with the ability to monitor PKM2 activity. A PET scan is a procedure in which a small amount of a radioactive substance, such as [18F]DASA-23, is injected into a vein, and a scanner is used to make detailed, computerized pictures of areas inside the brain where the substance is used. Glioblastoma tumor cells usually pick up more of these radioactive substances, allowing them to be found. Giving [18F]DASA-23 with a PET scan may help doctors evaluate PKM2 expression in patients with recurrent glioblastoma. The aim of this study is to determine whether the change in the [18F]DASA-23 PET scan signal from prior to therapy to after initiation of therapy in recurrent glioblastoma patients can predict their progression-free survival. If successful, this study could potentially help to prolong the survival of patients with recurrent glioblastoma, by notifying their doctors earlier on in the treatment course whether a particular therapy may not be working against the tumor.
"Diagnostics and Management of Colorectal Cancer and Precancerous Polyps"
Laboratory Based Investigator: Shan Wang, Materials Science and Engineering and Electrical Engineering
Clinical Based Investigator: Uri Ladabaum, Medicine - Gastroenterology and Hepatology
The early diagnosis of cancer is a significant prognosticator for patient survival. Specifically for colorectal cancer (CRC), colonoscopy is an excellent tool for screening and early diagnosis of cancer, but unfortunately not everyone who should be getting a colonoscopy is. The discomfort and invasiveness of a colonoscopy dissuades many at-risk persons from obtaining one, but surveys have shown a higher compliance with recommended CRC screening guidelines is possible with a blood-based test. The collaboration between Profs. Wang and Ladabaum would allow for the development of a blood-based screening test for CRC by analyzing tumor-derived molecular markers present in blood. This assay would test for the abnormal hypermethylation of tumor suppressor genes in circulating tumor (ct) DNA, which is a hallmark of cancer development. Analyzing ctDNA in the bloodstream is very much a needle-in-a-haystack problem, and Prof. Wang has developed extremely sensitive tools for magnetic capture and analysis of ctDNA from blood, and its molecular analysis on biosensors, for a panel of methylated markers. Prof. Ladabaum would aid in using this technology in the clinic to assess its performance on actual cancerous patients. Collaborations such as this provide a necessary step toward translating fundamental scientific discoveries into tests with clinical utility.