Deadline is Friday, March 31.
This grant is designed to support residents or fellows who are planning a career focusing primarily on basic science or clinical research. It is designed for the exceptional trainee and implies dedication to a career in research.
You are eligible if:
Three grants of up to $25,000 each will be awarded. Each project is for one year. The recipients are expected to devote 75 percent of their professional effort toward the goals of this award.
Complete the application online. Paper applications are not accepted. View the award requirements and obligations.
The application site will be open from Monday, January 16, 2017 through Friday, March 31, 2017.
The start date for the 2017 awards was be July 1. For any questions please email the Scientific Affairs Department.
Redox imaging in cervical cancer as a predictive biomarker for traditional and novel therapeutics
John Floberg, 2016 Resident Seed Grant Awardee
Many women with cervical cancer relapse following definitive chemo-radiation therapy. One potential strategy to improve outcomes is to target redox pathways. Cervical cancer cells in an over-reduced state may be more resistant to oxidative stress. Novel therapeutics that shift cancer cells to a more oxidative state may therefore be beneficial. It may also be possible to image redox state (i.e. the oxidizing and reducing potential of cells) using [Cu-64]-copper(II)-diacetyl-bis(4- methylthiosemicarbazonato) ([Cu-64]-ATSM) positron emission tomography (PET), potentially combined with 2-deoxy-2-[F-18]-fluoro-D-glucose ([F-18]-FDG PET) and magnetic resonance imaging (MRI). Imaging biomarkers representative of redox state might therefore be predictive of response to therapy, and identify patients who will benefit from novel therapeutic strategies.
The proposed study aims to characterize redox state of cervical cancer using multi-modality imaging, including [Cu-64]-ATSM PET, [F-18]-FDG PET, and diffusion weighted MRI (DWI), and to show that these metrics are predictive of response to traditional therapy, and novel therapies targeting redox pathways. This will be done in both in vitro and in vivo models of cervical cancer.
Glutamine Metabolism to Overcome Radioresistance in Non-Small Cell Lung Cancer
Chirayu Patel, 2016 Resident Seed Grant Awardee
Survival in advanced NSCLC remains limited despite targeted
therapeutics and immune checkpoint inhibitors. Targeting cellular metabolism
via inhibition of glutamine (Gln) uptake transport and metabolism is a novel
treatment strategy: First, the hypoxic cancer microenvironment leads cancer to
metabolically depend on glutamine (Gln) rather than glucose. Second, the
resultant shift to Gln metabolism contributes to radioresistance as
radiotherapy thrives on oxygen-related injury for DNA damage and apoptosis via
reactive oxygen species (ROS) production. Glutamine is metabolized by
glutaminase to glutamate, which is then used to synthesize glutathione, a
scavenger for reactive oxygen species (ROS). Thus, targeting Gln transport and
metabolism may render cells more sensitive to apoptosis. Third, to facilitate
the translation of basic science discoveries regarding glutamine metabolism to
impact patients, our laboratory is developing small molecule inhibitors (SMI)
of clinically relevant amino acid transporters and has been authorized by
Calithera Biosciences to conduct in vitro and in vivo studies using CB-839, a
first-in-class selective, reversible, and orally bioavailable glutaminase
inhibitor, which has undergone phase I clinical trials with a favorable safety
profile. We hypothesize that upregulated glutamine metabolism in NSCLC leads to
radioresistance via a ROS-dependent mechanism - targeting glutamine metabolism
will radiosensitize NSCLC, both in lung cancer cell lines and a xenograft
model. In aim 1, I will test the hypothesis that SLC1A5 overexpression supports
lung cancer cells’ addiction to glutamine and renders them resistant to
radiation therapy, which can be overcome with genetic or pharmacologic
inhibition of SLC1A5 or glutaminase inhibition. In aim 2, I will determine the
feasibility and efficacy of targeting glutamine metabolism using CB-839 in a
xenograft mouse model of a lung cancer cell line overexpressing SLC1A5, with
and without radiotherapy. Glutaminase targeting will be confirmed through
metabolite analysis and in vivo ROS levels will be determined. With this
experience, I expect to generate preliminary data to conduct an
investigator-initiated clinical trial to examine the synergy between
pharmacologic glutamine pathway inhibition and radiation therapy in NSCLC.
Through the skills I will develop, I hope to complete a post-doctoral
fellowship after residency and compete for a physician-scientist junior faculty position in radiation oncology.
Focused Ultrasound-induced blood brain barrier disruption in checkpoint blockade immunotherapy and the abscopal effect
Cheng-Chia Wu, 2016 Resident Seed Grant Awardee
Cancer immunotherapy is a growing field for the treatment of melanoma. Since the seminal studies examining the role of CTLA-4 (Cytotoxic T-Lymphocyte Antigen-4) in metastatic melanoma, immunotherapy targeting checkpoint inhibitors CTLA-4 and PD-1 (Programmed Death-1) have been recommended as accepted treatment for metastatic or unresectable disease. Furthermore, initial case reports by Postow and colleagues, preclinical models, and retrospective studies have shown that the addition of radiation therapy can further promote this effect through the abscopal effect. Historically, the central nervous system (CNS) was thought to be an immune privileged site protected by the blood brain barrier (BBB). Clinical scenarios such as infectious encephalitis and autoimmune demyelinating disease suggest there is a degree of immune surveillance in the CNS in which lymphatic drainage, CNS antigen presentation niche, and the BBB may play a role. Our hypothesis is that the integrity of the blood brain barrier may limit cross talk between the CNS and systemic immune system to checkpoint inhibitor targeted therapy and abscopal effect for intracranial metastatic melanoma. Disruption of the blood brain barrier with focused ultrasound (FUS) can enhance the immune response and the abscopal effect in the brain. The use of FUS to disrupt the BBB in the setting of checkpoint blockade immunotherapy and radiation induced abscopal effect has not been explored. This is a novel project with clinical implications as the first patient treated with FUS to disrupt the BBB was recently performed in November 2015. The proposed study will assist the applicant in pursuing an academic career with a focus in technology, neuroimmunology, and radiation oncology.
Ariel Marciscano, 2015 Resident Seed Grant Awardee
Over the past two decades the development of therapeutic monoclonal antibodies (mAbs) has led to considerable progress in the goal of achieving personalized cancer medicine. More recently, cancer immunotherapies, specifically immune checkpoint blockade mAbs have demonstrated significant efficacy and durable clinical responses in a proportion of patients across multiple cancer subtypes. There is now an expanding body of evidence that combining radiotherapy (RT) with immune checkpoint blockade can enhance anti-tumor immune responses and increase the therapeutic efficacy of RT.
Due to the rapidity at which immune checkpoint mAbs have been translated into clinical practice there is currently a paucity of prognostic or predictive biomarkers. High pre-treatment levels of Programmed Death-Ligand 1 (PD-L1) expression within the tumor microenvironment (TME) have correlated with response to anti-programmed death-1 (anti-PD-1) and anti-PD-L1 blockade. Data from our laboratory and others has suggested that stereotactic RT and anti-PD-1 treatment synergistically promotes anti-tumor immunity and enriches tumor-specific effector T-cell function. However, the mechanism of synergy between RT and anti-PD-1 is poorly understood and the impact of RT upon the tumor microenvironment and PD-L1 expression is yet to be defined.
The aims of this study are to use immuno-Positron Emission Tomography (immuno-PET) in order to:
Immuno-PET is an emerging oncologic molecular imaging modality that utilizes radiolabeled mAbs directed at TME targets. The advent of immune checkpoint blockade provides a highly relevant and unique opportunity to apply immuno-PET to anti-PD-L1 mAbs. In vivo quantitative assessment of 89Zr-anti-PD-L1 over several time points can describe RT and anti-PD-1 blockade modulation of the TME thereby elucidating potential mechanisms of synergy. To our knowledge, this is a novel application of immuno-PET and the development of 89Zr-anti-PD-L1 as a non-invasive imaging biomarker would have tremendous clinical implications for both RT and immunotherapies moving forward.
As we enter a potential paradigm shift in the era of cancer immunotherapy, improving our understanding of the host immune system and TME will be critical. Immuno-PET is a non-invasive tool that has the potential to help optimize the combination of stereotactic RT and immune checkpoint blockade and identify subsets of patients that will benefit from these therapies.
David Mayhew, 2015 Resident Seed Grant Awardee
The regulation of mRNA translation/protein synthesis is rapidly gaining interest in the field of cancer biology. Due to its fundamental dysregulation in cancer and its adaptive alterations in response to existing therapies, mRNA translation is increasingly recognized as a viable yet underutilized therapeutic target. Alternative mRNA translation strategies that do not use the canonical 5’-cap of the mRNA to engage the ribosome, such as those utilizing internal ribosome entry site (IRES) dependent mechanisms, may indeed play an important role in cancer progression. IRES translation is poorly understood, yet many oncogene and proto-oncogenes utilize IRES translation to regulate their expression, suggesting that IRES-regulated proteins may be involved in cancer treatment response and resistance. We will study the role of IRES translation in the cellular stress response and its subsequent impact on treatment resistance in multiple breast cancer cell lines in vitro as well as tumor xenografts in vivo. Identification and characterization of IRES-regulated proteins will lead to potential therapeutic targets to combat treatment resistance in breast cancer.
Todd Aguilera, 2014 Resident Seed Grant Awardee
In recent years much has been learned about tumor associated antigens that the immune system uses to distinguish tumor cells and how the immune system can be activated to respond to cancer. Immune checkpoint inhibitors are a class of cancer therapeutics that arose from blocking inhibitory receptors that prevent a cancer immune response and have enabled dramatic antitumor responses in specific cases. Though there have been notable breakthroughs with this class of agents they are considered to be active primarily in immunogenic tumors. This project aims to investigate reasons why in the setting of checkpoint blockade tumor immunity often does not occur. It is hypothesized that radiation can play an important synergistic role in the setting of checkpoint blockade to enhance responses through increasing antigen presentation and altering immunosuppressive tumor lymphocytes. This study will also evaluate the ‘abscopal effect’ of radiation that when combined with immune checkpoint blockade can lead to immune responses to untreated tumors. There is need to validate the mechanistic hypotheses for these phenomena and apply them to poorly immunogenic tumors with the goal of developing a therapeutic regimen that can impact a broader number of cancers than currently capable with mono therapy. This study will evaluate how PD-1 inhibition synergizes with radiation. It will explore methodologies that exploit the emerging hypotheses of adaptive immune resistance and de novo antitumor response. Tumors that respond to checkpoint inhibition alone by expressing tumor antigen will be compared with poorly immunogenic tumors, and new combination approaches that include radiation will be explored. This proposal aims to unveil important aspects of tumor immunity allowing a greater impact of immune checkpoint targeted therapeutics.
Tu Dan, 2014 Resident Seed Grant Awardee
Breast cancer is known to be a heterogeneous disease entity. While the majority of women have favorable outcomes, there is a subset of women with disease resistant to standard treatments. These tumors are often associated with basal-like gene expression and triple negative receptor status. Triple negative breast cancers (TNBC) have been found to have similar features as BRCA-defective tumors, leading to similar use of targeted therapies exploiting existing DNA-repair defects in this population. However, although successful in BRCA-mutated cancers, clinical studies targeting DNA repair pathways have been equivocal in TNBCs, leading some to believe that these cancers may be more resistant to DNA damage than previously thought.
Recent data has implicated the role of oncogenic microRNAs in driving treatment resistance. miR-21, in particular, has been found to be up-regulated in over 18 major cancer types and has been linked to radiation and chemotherapy resistance. It is associated with genes involved in DNA repair, cell cycle redistribution, tumor hypoxia, and has been experimentally found to target known tumor suppressors. Our laboratory has previously shown that miR-21 plays a role in the stress response induced by radiation-linked to DNA damage. We have demonstrated increased radiosensitivity in vitro when knocking down miR-21 in multiple radioresistant breast cancer cell lines. We have also generated a miR-21 knock out mouse demonstrating more than 2-fold increase in radiosensitivity than its wild type counterparts. Radiated tissue from these mice also reveal more double strand breaks than those of radiated wild type mice. In silico analysis indicates multiple targets of miR-21 involved in DNA repair mechanisms such as homologous recombination, particularly with targets in the cohesin complex, a highly conserved protein complex involved in DNA repair and replication.
We hypothesize that miR-21 up-regulation drives radiation resistance in breast cancers via alterations in the cohesin complex. Inhibition of miR-21 may be a novel approach to overcome treatment resistance and sensitize tumors to DNA-damaging agents. These findings would further elucidate mechanisms regarding treatment resistance and potentially augment existing therapeutics in a population of patients with poor prognosis and limited treatment options.
Zachary Morris, 2014 Resident Seed Grant Awardee
Evasion of immune detection is essential to the progression of malignancy. Immunotherapies elicit an anti-tumor response by engaging the immune system to recognize and eliminate tumor cells. A growing body of evidence suggests radiation may compliment immunotherapies by enhancing the immune susceptibility of tumor cells and generating tumor-specific antigens. We have been investigating the synergy of radiation and antibody-dependent cell-mediated cytotoxicity (ADCC) in a syngeneic murine model of melanoma. In these studies we have observed therapeutic cooperation of radiation and ADCC with respect to local tumor control without clear evidence of a systemic or memory T cell response. This is consistent with prior studies, which indicate that cells of the innate immune system principally mediate ADCC. Prior studies from other labs have demonstrated cooperation and modest rates of systemic T cell response when combining radiation and T cell checkpoint inhibitors, which enhance T cell activation. Given the complementary roles of the innate and adaptive immune system as well as the critical role of innate immune cells in priming adaptive immune response, we hypothesize that a therapeutic approach combining radiation, tumor-specific ADCC, and a T cell checkpoint inhibitor may synergize to augment local, systemic, and memory anti-tumor immune responses. Using a syngeneic mouse model of melanoma, we will test this hypothesis in vivo by comparing the efficacy of combinations of radiation, a tumor specific antibody that elicits ADCC, and a checkpoint inhibitor with respect to the control of local, distant (non-radiated), and re-introduced sites of disease. Using flow cytometry and immunofluorescence microscopy we will quantitatively and
qualitatively evaluate the immune response generated by these treatments. Results from this translational study will inform our understanding of the interactions between radiotherapy and the innate and adaptive immune system and will guide future clinical investigation.
Andrew Sharabi, 2013 Resident Seed Grant Awardee
One of the most desirable attributes of the immune system is the ability to develop highly specific and systemic responses to antigens. In the past, cytotoxic therapies such as chemotherapy and radiation were thought to suppress the immune system. However, recent data have shown that radiation can induce changes in tumor cells which promote immune responses and increase tumor susceptibility to immune-mediated cell death. Additionally, monoclonal antibodies which block negative regulators or checkpoints of the immune system such as CTLA-4 and PD-1 are gaining recognition as immunotherapy agents which can enhance immune responses in multiple different tumor types. Interestingly, when radiation is used in combination with these monoclonal antibodies there is preclinical data and case reports of robust immune responses and long term systemic tumor control. Furthermore, recent provocative evidence in breast cancer, colorectal cancer, and melanoma suggests that focused radiation can in fact stimulate an anti-tumor immune response which can act at distant sites outside of the radiation field, termed the Abscopal effect.
Our hypothesis is that the strategic use of radiation combined with novel immunotherapy agents will lead to synergistic effects and improved clinical outcomes due to radiation induced antigen specific immune responses (abscopal effect). We propose to investigate many fundamental questions regarding the abscopal effect with the following specific aims:
Specific Aim 1: Determine the optimal dose and fractionation for generation of radiation induced antigen specific immune responses. We will generate antigen-specific in vivo mouse models of the abscopal effect based on the previously described MCA38 cancer cell line. Our small animal radiation research platform (SARRP) will be used to deliver stereotactic image-guided radiotherapy with clinically relevant doses and fractionation. We will then systematically quantify the effects of total dose, dose per fraction, number of fractions, and biologically equivalent dose to optimize radiation induced antigen specific immune responses.
Specific Aim 2: Characterize the pre-clinical effects of anti-PD1 antibody on the magnitude and duration of radiation induced antigen specific immune responses (abscopal effect). We will characterize the role anti-PD1 Ab in augmenting abscopal responses when given concurrently with radiation. The effect of varied timing and frequency of anti-PD1 Ab on the magnitude of immune and memory T-cell responses will also be characterized.
Overall, these Specific Aims will answer critical fundamental questions regarding radiation induced immune responses. Specific Aim 1 has the potential to identify the optimal radiation dose and fractionation for induction of immune responses. Specific Aim 2 would provide pre-clinical evidence for a novel treatment paradigm of combining stereotactic radiotherapy with anti-PD1 Ab for improved loco-regional and distant control.
Gregory Gan, 2013 Resident Seed Grant Awardee
Background: The epidermal growth factor receptor (EGFR) is preferentially expressed in HPV negative (HPV-) head/neck squamous cell carcinomas (HNSCC) and is associated with a more aggressive phenotype. Resistance to EGFR blockade and radiotherapy (RT) remains a significant problem for both locoregional and distant tumor control due to accelerated repopulation mediated by the Hedgehog Pathway (HhP) and the Epithelial to Mesenchymal Transition (EMT). Our lab has demonstrated that the HhP is upregulated in response to RT both acutely and in chronically irradiated cell lines and this can be suppressed with the HhP inhibitor, cyclopamine. Preliminary mouse xenograft studies have shown that dual therapy with RT and cyclopamine is associated with improved tumor control. However, the molecular mechanism for GLI1 nuclear translocation following RT and what role GLI1 plays on the tumor microenvironment remain unknown.
Specific Aims: (1) Determine whether the DNA damage response pathway effects GLI1 translocation into the nucleus following RT and (2) Determine whether HhP inhibition of tumor stroma/microenvironment contributes to enhanced tumor control following RT in vivo.
Study Design: (1) We will evaluate GLI1 translocation into the nucleus using immunoblot and immunohistochemistry (IHC) following RT using commercial HNSCC cell lines and a GLI1 overexpressing cell line. Using a combination of siRNA and kinase specific inhibitors, we will determine whether ATM, ATR or DNA-PK pathways and whether the downstream effectors AKT and S6K1 are associated with GLI1 translocation. (2) We will implant HNSCC cell lines or patient-derived HNSCC tumor xenografts using a floor of mouth model; these animals will be treated with either RT, cyclopamine, or both and their tumors excised during and at the termination of treatment. Tumor and surrounding stroma will be evaluated using IHC and laser-capture microdissection/quantititative RT-PCR for GLI1 expression in addition to evaluating apoptosis via cleaved caspase 3 through IHC. We will also evaluate the long-term tumor control rates associated with monotherapy versus dual therapy. In a parallel pharmacodynamic study using the same 4 groups, we will flow sort stromal and tumor cells derived from these 4 groups and mix them 1:1 with untreated tumor cells and evaluate tumor regrowth kinetics in newly implanted mice.
Significance: Elucidating GLI1 nuclear translocation and its expression in the microenvironment of head/neck cancer following RT will provide a better molecular understanding of GLI1 regulation and whether stromal GLI1 expression in vivo is associated with tumor survival following genotoxic stress. This knowledge could then be used to more intelligently combine targeted agents that synergize with RT and HhP inhibitors.
Darrion Mitchell, 2013 Resident Seed Grant Awardee
Metastasis is an underlying cause of cancer mortality. Although improved treatments have increased overall survival and improved quality of life for cancer patients, there is much progress to be made in developing treatments for advanced metastatic cancer, including prostate cancer. Epithelial to mesenchymal transition (EMT) is a well-documented phenomenon important for both embryonic development in mammals and metastatic invasion in malignancies. EMT also serves as a mechanism enabling metastatic foci to develop resistance to radio- and chemotherapy. Published data indicate autophagy may be partly responsible for therapeutic resistance. Autophagy is a cellular process that removes damaged organelles, such as mitochondria and intracellular molecules, from cells enabling them to sustain metabolism and function. However, whether autophagy is linked to EMT-like states is unknown. Preliminary data from our lab show elevated autophagy in prostate cancer cells in an EMT-like state. Genetic inhibition of autophagy via knock down of the autophagy-mediating protein ATG5 in TEM 4-18 cells led to decreased cell survival under conditions of energetic stress. Our lab has also shown pharmacological inhibition via chloroquine leads to decreased autophagy and subsequent cell death. Chloroquine inhibits autophagy in breast, pharyngeal, and cervical cancer cell lines. Data from our lab shows it inhibits autophagy in prostate cancer cells as well. Our first aim will determine if inhibiting autophagy by chloroquine leads to radiosensitization of prostate cancer cells in the EMT-like state by increasing oxidative stress. Our second aim focuses on identifying novel small molecules that are selectively cytotoxic to prostate cancer cells in the EMT-like state via the development of a high-throughput assay. We will investigate fifteen novel chloroquine analogs and many other compounds via the Microsource 2300 library. Our long term goal is that this work will substantially improve our current management of metastatic disease, contributing to the advancement of targeted therapy for not only prostate cancer metastasis but other cancers as well.