The Junior Faculty Award (JFA) was created for faculty in early stages of their career to explore opportunities in research. It provides an opportunity to have focused time for research projects in radiation oncology, biology or physics and provides funds to generate pilot data that can be used for future federal funding applications.
You are eligible if:
In addition, the mentor and a responsible member of the institution/department must demonstrate, in writing, a commitment to your development as a productive, independent investigator.
One junior faculty is selected annually for this award, which provides $100,000 each year for two years. Recipients may be eligible for a competitive renewal of the award for a third year.
At least 50 percent of the recipient’s full-time professional effort must be devoted to the goals of this award. The remainder may be devoted to clinical, teaching or other research pursuits consistent with the objectives of the award. The successful candidate is expected, toward the end of the award period, to apply for grant support through NIH or other national funding mechanisms, such as K08, K23 or equivalent awards.
Complete the application online. Paper applications are not accepted. The award requirements and obligations can be found below:
Award Requirements and Obligations
The application site will open on Wednesday, January 27, 2016 and will close on Friday, March 25, 2016.
The start date for 2016 awards will be July 1. For any questions please email the ASTRO research department.
Stephanie Markovina, 2016 JFA Awardee
Cervical cancer remains a common cause of cancer death worldwide, and recurrence after chemoradiation (CRT) is closely associated with death due to a lack of effective salvage therapies. Understanding underlying resistance mechanisms is paramount to developing more effective upfront therapies and improving outcomes for these women. We previously demonstrated that high serum squamous cell carcinoma antigen (SCCA) is prognostic for poor response to CRT, recurrence and death. SCCA is a protease inhibitor that protects tumor cells from cytotoxic stress. Its target proteases include lysosomal cathepsins (CTS), which are released during lysosomal membrane permeabilization (LMP), a distinct death-initiating event. LMP is upregulated in tumor cells, and is further induced by cytotoxic stressors including reactive oxygen species and DNA-damage, signals generated by ionizing radiation (IR). The role of SCCA in the pathogenesis of cervical cancer is not well understood. Our preliminary data suggest that stress response expression profiles are enriched in tumors from patients with elevated serum SCCA, an SCCA-specific immunohistochemical signature is associated with recurrence and death, and SCCA is increased in response to IR. Using patient specimens, transcriptome analysis, and engineered cell line and mouse models, this proposal tests the hypothesis that elevated serum SCCA is a marker of stress response profiles in mid-treatment tumors, and that SCCA mediates cervical cancer resistance to IR by blocking LMP-mediated death. The goal of these studies is to better understand resistance mechanisms in order to develop more effective therapies and improve outcomes for women with cervical cancer.
Kent Mouw, 2015 JFA Awardee
Despite advances in radiation delivery techniques, the overall treatment paradigm for locally advanced anal cancer has changed little in the past 30 years. Although a combination of cytotoxic chemotherapy and radiation is successful in curing a majority of patients, a subset of patients fail primary therapy and require salvage surgery or develop metastatic disease. In addition, treatment can be associated with significant acute and long-term toxicities.
Recent advances in genomic techniques have led to characterization of the molecular features of many tumor types as well as identification of potential therapeutic targets. However, little genomic data exists for anal cancer, and personalized treatment approaches based on tumor genetic features are currently not available. In this proposal, we aim to map the genetic landscape of a large number of anal tumors in an effort to better understand anal cancer biology and identify therapeutic targets. In addition, we hypothesize that correlating genomic features with available clinical information will identify relevant biomarkers of treatment response and disease outcome.
We have performed whole exome sequencing of tumor and matched normal DNA from a pilot cohort of patients with locally advanced anal cancer treated with concurrent chemoradiation at our institution. The pilot cohort was selected to include patients who had complete response to treatment and were free from recurrence during follow-up as well as patients with residual or recurrent disease. For patients with residual or recurrent disease, both the primary and residual/recurrent tumors were sequenced. Preliminary analysis identified unique gene copy number alterations as well as recurrent mutations in several known cancer genes such as FBXW7 and PIK3CA. In addition, analysis of paired primary and recurrent tumors reveals surprising mutational heterogeneity, providing genetic evidence that some disease recurrences may be driven by development of a second primary tumor rather than outgrowth of the original tumor. To our knowledge, this is the first genome-level analysis of treatment response in anal cancer.
To extend our study, we propose to fully sequence more than 550 known cancer genes in a larger institutional cohort of locally-advanced anal cancer cases treated with chemoradiation. We anticipate that correlating the mutational features of these tumors with the available clinical data will provide unique insight into the genetic features governing tumor behavior and treatment response. We then aim to expand and validate these findings by performing a similar analysis in a large cohort of patients treated on multi-institutional prospective anal cancer clinical trials. We believe that interpreting existing clinical information in the context of novel genomic data will provide a unique opportunity to advance personalized treatment and improve outcomes for anal cancer patients.
Robert Mutter, 2015 JFA Awardee
Background:TNBC is an aggressive subtype that may be further classified based on the status of the DNA repair pathway of homologous recombination(HR). HR is required for error-free DNA double strand break repair. Emerging data suggests that TNBC with deficient HR is relatively chemosensitive, whereas HR proficient TNBC is more chemoresistant. Patients with residual TNBC after preoperative chemotherapy (i.e. chemoresistant disease) have a high risk of recurrence and death despite surgical resection and radiotherapy (RT).
Objective/hypothesis:Considering the importance of HR on TNBC chemosensitivity, and the high rates of locoregional recurrence in chemoresistant disease, we hypothesize that proficient HR function and associated chemoresistance predicts for a more radioresistant phenotype than HR deficient TNBC. As a result, the one size fits all RT that characterizes practice today may not adequately treat patients with chemoresistant TNBC and a therapeutic window for cure may be lost prior to systemic dissemination. Ubiquitin specific protease 13 (USP-13) is significantly overexpressed in TNBC. Our preliminary data demonstrates that USP-13 is an important regulator of HR through interaction with BRCA1, and therefore USP-13 is a novel therapeutic target to overcome resistance. We hypothesize that USP-13 inhibition will enhance the radiosensitivity of HR proficient/chemoresistant TNBC by inhibiting HR-mediated DNA repair.
Specific aims:1.determine whether TNBC chemoresistance predicts radioresistance, and correlate radiosensitivity with function of the DNA repair pathway of HR; 2.investigate whether USP-13 is a determinant of RT response and potential therapeutic target to overcome resistance in HR proficient TNBC.
Study design:The principal pre-clinical models to be used in this work are TNBC xenografts established from primary tumors of high risk breast cancer patients enrolled on the Mayo Breast Cancer Genome Guided Therapy Study. Tumor biopsy samples were obtained prior to the initiation of standard of care taxane and anthracycline based preoperative chemotherapy. In addition, residual tumor samples following chemotherapy were obtained at the time of surgical resection. Xenografts were developed by directly implanting these breast tumor tissues into SCID mice. The xenografts maintain key histologic and molecular features of the original human tumor and each corresponding human tumor has been comprehensively characterized with whole exome sequencing and RNA sequence analyses. We will use this unique panel of chemosensitive and chemoresistant TNBC models to assay HR function, examine radiosensitivity, and determine the therapeutic impact of USP-13 inhibition.
Bryan Allen, 2014 JFA Awardee
Lung cancer has the highest cause of cancer related mortality in the world causing approximately 1.2 million deaths per year. Approximately 75 percent of all lung cancers are classified as non-small cell lung cancer (NSCLC) which includes adenocarcinoma, squamous cell carcinoma and large cell carcinoma. The majority of NSCLCs over-express the epidermal growth factor receptor (EGFR) which is involved in anti-apoptotic and cell proliferation pathways. Many EGFR antagonists have been developed and are used both as single agents as well as complements to radiation and chemotherapy. Despite these advances, the overall NSCLC 5 yr survival rate continues to be poor at approximately 14 percent.
Thus, additional non-toxic approaches that enhance radiation and chemotherapy while complementing EGFR antagonism are needed.
Data suggest that cancer cells have defects in mitochondrial metabolism increasing the production of superoxide and hydrogen peroxide. Thus cancer cells are proposed to exist in a state of oxidative stress and therapies that further increase oxidative stress may be exploited to increase the sensitivity of radiation therapy and/or chemotherapy.
Ketogenic diets are high in fat and low in protein and carbohydrates and force cells to rely more on lipid oxidation and aerobic respiration than glycolysis for energy production. In addition, inhibition of the EGFR pathway is associated with the activation of c-Jun N terminal kinase 1 (JNK1) which is reported to induce oxidative stress. Since cancer cells have defective oxygen metabolism which causes chronic metabolic oxidative stress and because ketogenic diets force cancer cells to rely more heavily on oxygen metabolism to generate energy, then ketogenic diets would be expected to selectively cause oxidative stress in cancer cells. In addition, if intracellular reactive oxygen species are increased via EGFR inhibition, then there may be a beneficial effect of combining a ketogenic diet with anti-EGFR targeted therapies. Using this rational, we hypothesize that a ketogenic diet combined with anti-EGFR targeted therapy will enhance radio-chemosensitization in NSCLC cells by a mechanism that increases oxidative stress induced cell killing. In our first aim, we will determine if a ketogenic diet in combination with an EGFR inhibitor enhances chemo-radio-sensitization by a mechanism that involves oxidative stress in vitro. Our second aim address whether a ketogenic diet, in combination with an EGFR inhibitor, enhances the sensitivity of NSCLC cells to chemotherapy and radiation by prolonging animal survival and decreasing tumor growth rate in mouse NSCLC xenograft models.
Stephen Shiao, 2014 JFA Awardee
Breast Cancer remains the most common cancer in North America and the second leading cause of cancer death in women. Radiation therapy (RT) plays an integral part in the treatment of breast cancer with more than half of all breast cancer patients receiving radiation sometime during the course of their treatment. The conventional view of RT has largely focused on the effect of RT on the tumor cells themselves. However, recent studies have demonstrated a critical role for the immune system in determining the response of tumors to RT. Multiple studies have identified macrophages as key cells that regulate the immune response in tumors following RT. Macrophages have multiple different phenotypes that can either support or suppress an ongoing immune response and our preliminary data suggests that targeting a cytokine, interleukin(IL)-4, that controls the development of macrophages that suppress an ongoing immune response enhances the efficacy of RT. The objective of this research proposal is to address the mechanism(s) by which IL-4 blockade enhances the response to RT. The proposal tests the hypothesis that macrophage phenotype regulates RT-induced immune responses and that the efficacy of RT can be enhanced in vivo by IL-4 blockade. To evaluate this hypothesis, the following Aims are proposed: Aim 1: Characterize the effect of IL-4 blockade combined with RT on intra-tumor immune responses in a murine model of breast cancer and Aim 2: Define mechanism(s) of IL-4-regulation of RT responses in a murine model of breast cancer. We will accomplish these aims using focal RT in a murine model of breast cancer and studying the effects of RT and IL-4 blockade using a combination of flow cytometry, immunohistochemistry, quantitative PCR and ELISA to determine the changes in the immune profile of tumors. The significance of this research is that it will provide insights on the tumor immune response to radiation that may lead to new immune-based therapies for the treatment of breast cancer and multiple other solid tumors in which RT play an integral therapeutic role.
Joseph Mancias, 2013 JFA Awardee
Pancreatic ductal adenocarcinoma (PDAC) exhibits profound resistance to available therapies, thus there is a strong impetus to identify new therapeutic targets for this disease. Recent work has shown that autophagy is critical for PDAC growth and autophagy inhibition synergizes with radiation in PDAC cell lines. Therefore, autophagy inhibition may be useful clinically, especially in the setting of locally advanced PDAC. The goals of the proposed project are twofold: 1) to understand if autophagy inhibition promotes radiosensitization in PDAC tumors and 2) to identify new biomarkers to select for PDAC patients who may benefit from autophagy inhibition combined with radiotherapy and biomarkers to monitor autophagy inhibition. To address the first goal we will examine samples from an ongoing clinical trial of PDAC patients adding autophagy inhibition using hydroxychloroquine (HCQ) to preoperative chemoradiation prior to surgical resection and samples from a murine ‘co-clinical’ trial testing autophagy inhibition as a radiosensitizer in a PDAC mouse model. By analyzing human pre-treatment biopsies and post-treatment resected tumors and murine control versus treated animal tissues, we will determine if HCQ is inhibiting autophagy in human and murine PDAC tumors. In addition, we will investigate the molecular components of radiation response with the addition of HCQ in an attempt to elucidate the efficacy and determinants of HCQ radiosensitization. To identify new biomarkers to guide optimal patient selection for the combination of radiotherapy and autophagy inhibition and biomarkers to monitor autophagy inhibition, we will use a combination of quantitative proteomics, oncogenomics, cell biology, and biochemistry to study both human PDAC cell lines and murine/human PDAC tumor samples. Quantitative proteomics using mass spectrometry allows for relative quantification of expression levels of proteins in mixed samples on a whole proteome level. In contrast to microarray profiling of tumor tissue, quantitative mass spectrometry identifies changes in expression at the protein level, which would better translate into effective biomarkers for applications such as immunohistochemistry (IHC). We will initially focus on biomarker candidates with available IHC reagents and validate their clinical usefulness using clinical trial samples. The proposed research has the potential to improve the dismal prognosis of pancreatic cancer patients and to optimize the care of patients enrolled in clinical trials utilizing autophagy inhibition.
Terence Williams, 2013 JFA Awardee
KRAS activating mutations are a frequent somatic event in a number of human malignancies, including lung, pancreatic, and colorectal carcinomas as well as leukemia. These mutations appear to drive tumor dependency on the RAS-MAPK and AKT signaling pathways. As an example, KRAS mutations occur in greater than 90% of pancreatic cancer, and such an extremely high frequency is unique to this cancer type. There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. Radiation is currently being explored in both the post-operative and inoperable settings as a component of the standard treatment regimen for pancreatic cancer. Local failure can be the primary cause of death for about one-third of patients, and thus strategies aimed at improving local control could potentially have an impact on improving survival. Recent clinical trials from ECOG and Japan have established the superiority of adding radiation to chemotherapy for unresectable pancreatic cancer. Thus, strategies directed at improving radiation efficacy could improve survival for patients with pancreatic cancer. Numerous reports provide evidence that hyper-activation of the RAS-MAPK pathway can lead to development of radioresistance. MEK-1/2 are kinases further downstream of KRAS (immediately downstream of RAF kinases), and are directly responsible for activating ERK-1/2. Thus, MEK plays a pivotal downstream role, and is of high interest in KRAS mutated cancers. MEK inhibitors are currently being tested in phase I clinical trials to treat various tumor types alone or in combination with chemotherapy, particularly for those tumor types that have a high frequency of KRAS or BRAF activating mutations, with reports showing improved objective responses. My preliminary data demonstrates that radiation up-regulates ERK-1/2 activation, and that inhibition of ERK-1/2 activation by upstream MEK inhibition can radiosensitize pancreatic cancer cells. Additionally, alterations in DNA damage response pathways with MEK inhibition have been identified. Furthermore, AKT is activated with radiation and appears to partially mediate resistance to MEK inhibition. Combined MEK and AKT inhibition with or without radiation has the most profound inhibitory effect on cell growth and survival. The specific aims of my proposed studies are to:
I hypothesize that MEK inhibitors will offer clear therapeutic benefit when integrated into chemo- and radiotherapy treatment regimens in current use for the treatment of pancreatic cancer. Additionally, I hypothesize that pathways which mediate resistance to MEK inhibitors and novel pathways whose inhibition offers synthetic lethality with MEK inhibitors can be identified and successfully targeted. The proposed approach utilizes a combination of molecular signaling pathway analysis and molecular imaging to define a treatment and biomarker strategy for this mechanistic class of agents in combination with radiation. The impact of this project will be to improve treatment outcome for pancreatic cancer patients and to provide a prototype development approach applicable to other solid tumors with KRAS mutations (e.g. lung, colorectal), or other novel targets identified during the biomarker and resistance screens.