Past Funding Successes

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.

Dr. Alexandra Martin

Dr. Martin is a Cancer Researcher in the Clinical Science Department at Moffitt Cancer Center. She is investigating an innovative way of dosing PARP inhibitors, a common therapy for ovarian cancer in both treatment and maintenance settings. Rather than standard dosing, she uses adaptive therapy based on mathematical models and evolutionary principles to guide drug dosing and on-off cycling, with the goal of maintaining a stable tumor burden by allowing a population of treatment-sensitive cells to survive. Her work seeks to identify suitable biomarkers to further refine mathematical models for use in ovarian cancer patients to delay or prevent drug resistance and disease progression, decrease cumulative drug use, decrease toxicities, increase quality of life and save healthcare dollars.

2020/2022 Martin Research Project:

Optimization of poly ADP ribose polymerase (PARP) inhibitor dosing for ovarian, fallopian tube and primary peritoneal carcinoma using adaptive therapy

Despite many new developments in treatment, ovarian cancer remains a leading cause of death in women. Approximately 70% of ovarian cancer patients will experience recurrence of disease. This project will use retrospective data and mouse models to optimize mathematical models and determine the optimal dosing of PARP inhibitors for ovarian cancer patients based on changes in their tumor and bloodwork. The mathematical models will be used to run a clinical trial comparing standard dosing to adaptive therapy, with the goals of preventing or delaying drug resistance and disease recurrence, improving treatment-related toxicities and decreasing overall healthcare costs.

Dr. Heiko Enderling

Dr. Heiko Enderling is an Associate Member in the Integrated Mathematical Oncology Department at Moffitt Cancer Center. His research integrates mathematical, biological, and clinical sciences to model, simulate, and predict treatment response for individual patients. Models are created based on experimental data and historic clinical outcome data to develop, calibrate and validate the mathematical models of a certain disease and a certain treatment response. Once researchers have a model that is performing well, they integrate patient-specific data which is used to predict responses to treatments for individual patients on the computer or to run broader computerized clinical trials to find the best treatment. Dr. Heiko Enderling was recently named Fellow and elected President-elect of the Society for Mathematical Biology.

2020/2022 Enderling Research Project:

Simulating the effect of photoimmunotherapy on the ovarian cancer immune ecosystem

Despite advances in surgery and therapeutics, the survival of advanced or recurrent epithelial

ovarian cancer (EOC) remains dismal due in part to the complex tumor-immune microenvironment. This project will develop a computer model that simulates the effectiveness of using chemotherapy and immunotherapy in the treatment of epithelial ovarian cancer (EOC). The model can be adapted to develop, calibrate, and validate changes during photoimmunotherapy, and to identify optimal photoimmunotherapy dosage needed to stimulate anti-tumor immunity to target cells which can lead to metastatic disease.

Olga Guryanova, MD, PhD

Assistant Professor, UF College of Medicine
Department of Pharmacology & Therapeutics

The overarching research goal of the Guryanova Lab is to delineate the mechanisms of the cross-talk between epigenetics and chromatin organization, learning how these processes apply to the development of acute myeloid leukemia (AML), resistance to therapies, and clonal evolution. Ultimately, Dr. Guryanova would like to harness this mechanistic understanding to develop improved therapeutic approaches for leukemia.

2020: Novel combinatorial treatment approaches to augment sensitivity to cytarabine in acute myeloid leukemia with DNMT3A mutations

Mansour Mohamadzadeh, PhD

Professor, UF Colleges of Medicine and Veterinary Medicine

Department of Infectious Diseases & Immunology

Julie Bradley, MD

Assistant Professor, UF College of Medicine

Department of Radiation Oncology
UF Health Proton Therapy Institute

 2015: Prospective Pilot Study of Early Markers of Radiation Induced Cardiac Injury in Patients with Left Sided Breast Cancer

Maryam Rahman, MD

Assistant Professor, UF College of Medicine
Department of Neurological Surgery

2016: Using SR233 for Enhancing Cellular Migration in Dendritic Cell Vaccine Therapy for Malignant Brain Tumors

Hendrik Luesch, PhD

Professor And Chair, Debbie And Sylvia DeSantis Chair In Natural Products Drug Discovery And Development

UF College of Pharmacy
Department of Medicinal Chemistry

2016: Targeting Colon Cancer with a Novel Marine-Derived Selective Anticancer Agent