Research Projects

Meet the doctors and their research projects for ORD’s 2023/2024 funding cycle

Erin Dean, MD

Title of project:

Evaluating soluble B-cell maturation antigen as a new serum marker of minimal residual disease in patients with Multiple Myeloma

Description of project:

Multiple Myeloma (MM) is an incurable hematologic malignancy, originating in the plasma cells (a type of white blood cell) in the bone marrow, which affects patients at an average age of 70. Initial treatment involves induction therapy typically followed by autologous hematopoietic stem cell transplantation (HSCT) for consolidation of the initial response. Achieving and maintaining undetectable minimal residual disease (MRD) in the bone marrow with therapy has been associated with prolonged progression free survival and overall survival. While approved MRD testing exists to detect persistent disease and early relapse in the bone marrow, this requires repeated bone marrow biopsies (BMBx) to obtain bone marrow aspirate samples. This is costly, painful, and inconvenient to the patient; thus, this is impractical and not usually done in clinical practice. There are currently no reliable assays able to identify concomitant MRD disease in the peripheral blood. This project will address a critical unmet need and generate a practical, non-invasive way to assess how well the patient is responding to therapy and provide an early warning signal for progression of disease so treatment can be started on time to improve patient outcomes.

Joseph Markowitz, MD, PhD

Title of project:

Nitric oxide dependent response to adjuvant interferon therapy in melanoma.

Description of project:

In 2022 there are projected to be 99,789 diagnosed melanoma cases and 7,650 deaths. Most patients present with melanoma that can be surgically resected. However, many patients relapse and therefore systemic therapy after surgery was developed to prevent distant metastatic disease. The first FDA approved therapy after surgery (adjuvant therapy) was interferon α albeit at a high risk of toxicity. In the 2010s, antibodies were developed and approved for clinical use that target checkpoint molecules that function to inhibit the immune response to melanoma. The first antibody was ipilimumab which blocks the CTLA-4 receptor on a subset of immune cells called T cells. Pembrolizumab and Nivolumab followed which block another inhibitory receptor on T cells called PD-1. The antibodies increase relapse free survival after surgery. The anti-PD-1 antibodies have a slight advantage of relapse free survival and a significant advantage with regards to overall toxicity. However, many patients treated with adjuvant anti-PD-1 antibodies relapse with distant metastatic disease. Given the different mechanism of actions it is very likely that subgroups of patients that will respond to interferon α or anti-CTLA- 4 therapy that will not benefit from anti-PD-1 therapy. Recently, our group has published an immune cell signature including the levels of nitric oxide that predicts response to ipilimumab (anti-CTLA-4) therapy among melanoma patients undergoing adjuvant therapy after resection using a novel immune phenotyping tool. We also have access to the peripheral blood samples and the mRNA array data collected from FFPE tissue specimens from the eastern cooperative oncology group (ECOG) clinical trial – ECOG 1609 where adjuvant ipilimumab was compared to interferon α. In addition, we are collecting samples from anti-PD-1 in the adjuvant setting.

This pilot grant will apply our novel tool (MPATR) to test whether the nitric oxide immune signature in the peripheral blood samples collected from patients receiving interferon α in ECOG 1609 predicts for longer relapse free survival (RFS). We hypothesize that increases in nitric oxide in immune effector cells and decreased nitric oxide levels in immune suppressor cells are associated with defined transcriptomic/proteomic signatures and increased relapse free survival to interferon therapy. Future directions will compare the results for a parallel study for the anti-CTLA-4 cohort of the clinical trial and an internally collected anti-PD-1 cohort (funded separately). The goal of this line of work is to determine which patients will respond the best to which line of adjuvant therapy as there are clearly patients who benefit from each line of therapy. We are choosing therapy based on a small response rate effect in the general population and an improved toxicity profile. In addition, we will gain valuable information on the interferon and nitric oxide dependent mechanisms of resistance to anti-PD-1 therapy that can be utilized for future therapeutic development in melanoma.

Marilena Tauro, PhD

Title of project:

A novel autophagy protein to guide Triple Negative Breast Cancer (TNBC) treatment response

Description of project:

TNBC is an aggressive and incurable disease (1). Despite the initial response to chemotherapy (2), patients often relapse with resistant disease that has spread to other parts of the body (3). Our group has found that TNBC cells use a program known as autophagy (self-eating) to protect themselves against chemotherapy induced cell deaths (4) In our preliminary studies, we have found that a novel protein that regulates the autophagy pathway can be a good indicator of whether patients will progress rapidly to develop resistant disease. The overall goal of this proposal is to fully investigate whether the detection of a novel biomarker of autophagy known as ULK3 in TNBC biopsies can guide clinical decisions of treatment, improve risk stratification and tailor treatment intensity in patients. To this end we plan to test the levels of ULK3 at diagnosis in tissue biopsies and monitor their response to treatment.

The rationale for this project is built on our preclinical studies on TNBC patient biopsies commercially available (US Biomax, Inc), where tissue was probed for a variety of proteins important in activating alternative nutrition of cancer cells, such as autophagy during treatment. We discovered, for the first time, that ULK3 protein increases with the progressive stage of the disease and in response to certain pro-apoptotic treatments (6). These preliminary data support our hypothesis that the increased presence of this protein correlates with poorer overall survival of the patient. Our preliminary data focused mainly on Non-Hispanic White patients but in the current proposal we will have any opportunity to determine whether our hypotheses hold true for Hispanic patients which are a major underserved population in Moffitt’s catchment area.

We believe that results generated via this research will yield a powerful clinical tool for patient prognosis and in the treatment-decision making process (for example, radiation vs chemotherapy). Stratification of TNBC may also improve quality of life for the patient by not exposing them to “one size fits all” chemotherapy that can cause serious side-effects and ultimately may prove ineffective for their disease.

Fan Zhang

Title of project:

In situ program CAR-Macrophage against glioblastoma

Description of project:

Malignant gliomas are the most common and aggressive form of primary brain tumors. Although cancer immunotherapies have achieved tremendous progress in other cancer types, they have not been beneficial to glioma patients. A major obstacle for successful immunotherapy for glioma is the hostile immune-suppressed tumor microenvironment (TME) that limits treatment efficacy. Tumor-associated monocytes/macrophages (TAMs) are major component of TME. They are constantly being recruited to tumor in large numbers, where they help tumor to grow and spread. Current strategies to targeting TAMs for cancer treatment are inefficient, toxic, and are non-specific. To address these limitations, we propose a novel strategy by developing a ‘mRNA nanotherapeutics’ – a therapeutic platform being used in the COVID-19 vaccine, to reprogram tumor-promoting TAMs to recognize and actively clear glioma cells. If implemented into the clinic, this ‘off-the-shelf therapy’ would enable physicians to quickly re-activate immunity against tumors while avoiding toxic side effects. It also has the potential to abrogate the tumor resistance to current standard-of-care treatment.

About Jameel Muzaffar, MD

Title of project:

Gut microbiome/ metabolome as a predictor and modulator of response to immunotherapy in head and neck cancer.

Description of project:

Head and neck squamous cell cancer (HNSCC) represents an array of clinically heterogeneous cancers which have a high unmet need for effective treatment options1. Immunotherapy in the form of Immune checkpoint blocker(ICB) has revolutionized the treatment of many advanced cancers including head and neck cancers1. Overall survival in patients who respond to immunotherapy has increased remarkably compared to chemotherapeutic options. However, response rates to immunotherapy in HNSCC is 20% at best2. Hence there is an urgent need to investigate markers of response and evaluate strategies to improve response among these patients to improve their survival.

Accumulating evidence from various studies ,mostly in melanoma patients, support that the gut microbiome can predict and modulate immunotherapy responses, however these studies have yielded widely conflicting results in respect to microbiome signatures and diversity that correlate with response3,4, thus limiting any clinical applicability. To overcome this limitation and to generate better understanding of dynamic relationship between the gut microbiome and immunotherapy, we need to characterize longitudinal changes in gut microbiota and microbial metabolites and its association with antitumor ICB responses in HNSCC patients.

We propose the first pilot study to evaluate longitudinal changes in gut microbiome and metabolome in HNSCC patients treated with ICB to develop a predictive biomarker of response to immunotherapy. Further, we propose preclinical fecal microbiota transplant studies to elucidate gut microbiota mediated modulation of antitumor responses and generate mechanistic data underlying the antitumor immune modulation. Understanding of mechanistic pathway would lead to develop strategies to modulate the gut microbiome to improve treatment outcome of hundreds of thousands of patients with head and neck cancer.