Translational Archives - Page 18 of 30

Michael Engel, M.D., Ph.D.

Funded by the Dick Vitale Gala

Acute leukemias (acute myeloid leukemia—AML and acute lymphoid leukemia—ALL) are lifethreatening
cancers of the blood responsible for 40% of all childhood cancer deaths. For those who survive, life-altering side effects from conventional therapy are common. Despite progressively improved survival, these circumstances are far from ideal. To achieve better outcomes with fewer side effects, we need new treatments that target mechanisms of leukemia cell survival. By focusing on these adaptations we have discovered an “Achilles heel” in leukemia cell survival. We discovered that leukemia cells depend upon a partnership between two proteins, Growth Factor Independence-1 (GFI1) and Lysine Specific Demethylase-1 (LSD1) in order to survive. The GFI1—LSD1 complex promotes leukemia cell survival by blocking genes that cause cell death. Leukemia cells cannot survive without GFI1, even if LSD1 is present, nor can they survive without LSD1 even if GFI1 is present. This suggests that inhibitors of the GFI1—LSD1 axis can trigger leukemia cell death. To this end, we developed a new drug (SP-2577) that selectively inhibits LSD1, overriding pro-survival effects of the GFI1—LSD1 axis and triggering death of AML and ALL cells. Notably, SP-2577 causes death of leukemia cells that are resistant to other drugs currently used to treat leukemia, and thus may provide a treatment for patients with relapsed disease. Our proposal tests the addition of SP-2577 to established treatment regimens for patients with relapsed AML or ALL and validates markers of SP-2577 “on target” activity for future multi-institutional clinical trials.

Michael Deininger, Ph.D., M.D. & Thomas O’Hare, Ph.D.

Acute myeloid leukemia (AML) has the most dismal prognosis of all blood cancers, and >70% of AML
patients will succumb to their disease. Therapy is still based on a chemotherapy regimen developed more
than three decades ago and what little progress has been made is attributable to improvements in
supportive care. Although most patients initially respond to therapy, leukemia stem cells survive in
sanctuary sites of the bone marrow and eventually cause relapse and death. Intense research has identified the major DNA mutations in AML, but this knowledge has not led to therapeutic breakthroughs. To overcome this stalemate, our translational medicine research team has taken a function-first approach to identify vulnerabilities in AML cells that are independent of genetic mutations and continue despite protection afforded by the bone marrow. We discovered that cells from most AML patients are highly dependent on SIRT5, an enzyme that regulates energy metabolism, while normal controls are not dependent on SIRT5. As no clinical SIRT5 inhibitors exist, these results prompted us to conduct a search for new SIRT5 inhibitors. We identified a highly promising candidate (HCI-0250) as the starting point for the development of a clinical SIRT5 inhibitor. We will validate SIRT5 as a therapy target in AML using mouse models reflecting key aspects of the clinical disease. In parallel, we will develop a potent and selective SIRT5 inhibitor as a candidate for clinical trials in AML. If successful, our work may lead to a new treatment paradigm applicable to a majority of AML patients.

Vered Stearns, M.D. & Roisin Connolly, M.D.

Funded by the Stuart Scott Memorial Cancer Research Fund

Antibody treatments that block ‘immune checkpoints’ which prevent the immune system from fighting cancer, have resulted in impressive tumor shrinkage and long term survival in many patients with cancer. Results from studies in metastatic triple-negative breast cancer (TNBC) indicate promising activity but not yet the exceptional results seen in tumors known to be highly “immunogenic” or responsive to alterations in the immune system. Strategies to make TNBC “immunogenic” are therefore of great interest as they may result in long term control of TNBC. This is of particular relevance to minority groups such as the African American population, who often present with an aggressive TNBC with limited treatment options available.

Our collaborators at Johns Hopkins have laboratory data, suggesting that combining the histone deacetylase (HDAC) inhibitor entinostat with immune-checkpoint blockade (nivolumab and ipilimumab) led to eradication of breast tumors and long term cures. Research suggests that entinostat may alter the tumor environment by affecting the regulatory immune cells which can prevent immune-checkpoint agents from fighting cancer. This combination may thus be able to convert these traditionally “non-immunogenic” tumors into tumors which can respond to immune therapy.

We are thus conducting a phase I clinical trial of entinostat, nivolumab +/- ipilimumab in advanced solid tumors and patients with TNBC. We anticipate that the collection of blood and tumor specimens during the study will allow us to determine how these drugs are working in patients so we can develop future trials with the hope of significantly improving outcomes for patients with TNBC.

Victoria Bae-Jump, Ph.D., M.D.

Funded by the Stuart Scott Memorial Cancer Research Fund

Obesity and diabetes are associated with increased risk and worse outcomes for endometrial cancer (EC). African American (AA) women suffer a higher mortality from EC than Caucasian (CAU) women, and this may be in part due to greater rates of both obesity and diabetes among AA versus CAU patients. Metformin is a drug used in the treatment of type 2 diabetes. Our preliminary data finds that metformin has anti-cancer activity, due to its indirect effects within the body (decreased insulin/glucose) and direct effects on EC cells through inhibiting signaling pathways involved in metabolism, including suppression of fatty acid/lipid biosynthesis. Thus, it is logical that metformin may break the link between obesity and EC and emerge as a new targeted agent for the treatment of this cancer.

Our overall goal is to assess the contribution of indirect effects (via decreasing insulin and glucose levels) and direct effects (via inhibition of metabolic pathways and blunting of fatty acid/lipid biosynthesis) of metformin to its overall anti-cancer efficacy in (i) a clinically relevant EC mouse (obese/lean) model and (ii) an ongoing randomized phase 2/3 clinical trial evaluating metformin versus placebo, in combination with standard of care paclitaxel/carboplatin for the treatment of EC. We hypothesize that predictors of metformin response will include both molecular and metabolic biomarkers, specifically obesity, insulin resistance, upregulation of insulin/glucose signaling and heightened fatty acid/lipid biosynthesis, and this response may differ according to race. From this work, we hope to validate metformin as an innovative treatment strategy for obesity-driven EC.

Valsamo Anagnostou, Ph.D., M.D.

Immune targeted therapies, which stimulate the immune system to attach cancer have revolutionized
cancer treatment strategies. These successes have offered new therapeutic avenues for cancer patients,
especially for those with lung cancer. Despite the impressive clinical efficacy and duration of responses
observed, the fraction of patients with durable responses remains in the order of 20% and there is
therefore an unmet need to maximize efficacy of these treatments as well as identify the patients more
likely to respond. We propose to use clinical samples from 2 novel clinical trials that combine immune
targeted therapy with a different class of medicines, called epigenetic therapy. We have shown that
epigenetic therapy may attract immune cells to the cancer site therefore “priming” an anti-tumor immune response. We propose to pinpoint the mechanisms that mediate response and resistance to these therapies by looking at the genetic make-up of cancer cells as well as by studying the tumor microenvironment. We believe our comprehensive, cutting-edge scientific approach linked with ongoing or soon to start clinical trials will result in immediate clinical intervention initiatives and is consistent with our mission to deliver improved treatments to patients with lung cancer.

Stephan Grupp, Ph.D., M.D.

Funded by the Dick Vitale Gala in Memory of John Saunders

Immunotherapy has given hope to many patients with previously incurable cancers. One of the strongest new immunotherapy techniques is CD19-targeted cell therapy. This is a method of engineering T cells from a patient to attack their own cancer. B-ALL, a type of leukemia, is the most common cancer in kids. In B-ALL, CD19-targeted cell therapy has put over 90% of relapsed patients into remission within a month of receiving these engineered T cells. One problem is that some patients’ cancers learn to hide the CD19 target that these engineered T cells see. The lack of the target allows the cancer to hide from the T cells and come back. This can happen in more than 20% of patients. With this grant, we will explore an alternative target called CD22. CD22 is on more than 90% of B-ALL cells. We will use a combination of CD19-targeted T cells and a drug called inotuzumab that attacks CD22 to prevent the cancer cells from coming back, even if they can hide the CD19 target. We will also develop T cells to target CD22. First, we will move forward with a combination approach using the CD19 cells and the CD22 drug in B-ALL patients. Later, we may use T cells against both CD19 and CD22. Currently, bone marrow transplant is the best option for kids with relapsed disease, but this comes with many risks. As we increase the number of patients remaining in long-term remission with these cell therapies, we can see a future where fewer patients need to undergo the risks of bone marrow transplant.

Ravindra Uppaluri, M.D., Ph.D.

One of the most exciting frontiers in cancer treatment is the field of immunotherapy where beneficial effects have been observed in a broad range of cancers. The major goal of our project is to identify the determinants of immunotherapy success in patients with head and neck cancers. We are performing a novel clinical trial with an immunotherapy-targeted agent that allows the patient’s own immune system to control their cancer. Using samples from this trial, our goal is to understand why some patients do or do not respond to immunotherapy. We have assembled a multi-disciplinary team that will use genetic and immunologic tests on patient samples to clarify which patients may actually benefit from this powerful approach. These data will allow us to define a precision approach to immunotherapy and in addition will provide an improved biologic understanding of the mechanism of immunotherapeutic modalities.

Alexander Guimaraes, M.D., Ph.D.

The poor survival of pancreatic adenocarcinoma (PDAC) patients is due partly to diagnosis at late-stages, concomitant with relatively ineffective cytotoxic therapies. This poor chemotherapeutic response may relate to unique properties of the PDAC tumor microenvironment (e.g. poor perfusion, increased fibrous stroma), which may be a barrier to drug delivery. We hypothesize a link between tumor stroma and microvasculature and have developed a steady-state MRI method that quantifies microvascular imaging biomarkers to study PDAC, using long-lived FDA-approved intravascular magnetic nanoparticles (MNP). By applying these techniques to angiotensin receptor-blockade, which directly effects fibrous stroma, we have demonstrated sensitivity to vascular normalization, a direct correlation with histologic assays, and improved drug delivery as measured by 18F-5 fluorouracil (5FU) positron emission tomography (PET). Based on exciting results from the Coussens, Varner, Bar-Sagi and Simon laboratories indicating that B cell-regulated pathways foster PDAC progression, and two reports from the Levy and Soucek laboratories, indicating that therapeutic targeting of Bruton’s tyrosine kinase (BTK) reprograms the immune microenvironment in PDAC to normalize vasculature and mobilize CD8+ T cells resulting in improve efficacy of gemcitabine (Gem) chemotherapy, we propose to quantitatively evaluate microvascular changes following BTK inhibition. These provocative preclinical data are now being translated to the clinic in a funded (Stand-Up-2-Cancer (SU2C) Phase 2 trial). The goal of this proposal, therefore, is to test the hypothesis that MRI measures of tumor microvasculature using MNP are surrogate biomarkers of therapeutic response to BTK inhibition by validating in mouse models and translating in humans participating in this SU2C trial.

Michelle Monje Deisseroth, M.D., Ph.D.

Funded by the Dick Vitale Gala in memory of Lauren Hill

We have recently demonstrated that neuronal activity in the cerebral cortex can drive the growth of deadly brain tumors called high-grade gliomas. High-grade gliomas include tumors that affect children, teens and adults, such as glioblastoma, anaplastic oligodendroglioma and the childhood tumor diffuse intrinsic pontine glioma (DIPG). High-grade gliomas are the most lethal of all brain tumors. An important way that brain activity promotes the growth of these brain tumors is through release of a molecule called “neuroligin-3”. The purpose of this project is to develop a new therapy for these deadly brain cancers designed to sequester neuroligin-3 like a molecular sponge. We have shown that such a strategy is effective in principle, and now seek to test and optimize this strategy in preclinical models of high-grade glioma.

Aude Chapuis, M.D.

Research has advanced new anticancer drug therapies, saving many lives, but it is estimated that cancers will still kill more than half a million Americans specifically African and Hispanic Americans. New, safe and effective treatment approaches are urgently needed. Especially promising are treatments including cancer cells, through a large family of proteins called “T cell receptors” (AKA TCRs) which bind particular molecules associated with tumors Dr. Chapuis is an expert in identifying tumor antigens, genetically engineering matching TCRs, putting them in T cells and then infusing these enhanced methods to develop new engineered T cell therapies for patients for whom best available therapies are simply inadequate. For patients with non-leukemia patients, further optimizing methods that can also be used to target other antigens in tumors where WT1 is not expressed. She also proposes therapy after the safety of each is established for a broader future impact, including for other patients with urgent needs.