Funded in partnership with the American Kennel Club Canine Health Foundation
Bladder cancer or urothelial carcinoma (UC) affects approximately 40,000 dogs per year in the US with specific breeds including Scottish Terriers, West Highland White Terriers, Shetland Sheepdogs, Beagles, and Parson Russell Terriers being over-represented. Affected dogs usually display lower urinary tract clinical signs including bloody urine, frequent urination, difficulty and pain on urinating, and urinary outflow tract obstruction. Standard of care consists of anti-inflammatory drugs either alone or in combination with chemotherapy or radiation therapy. While these treatments can lead to stable disease for 6-12 months, they rarely lead to a cure, and most dogs eventually succumb to their disease. In human medicine, urinary bladder tumors have been shown to exhibit a high gene mutational burden which directly correlates with a favorable response to immune therapies. Canine UC exhibits a similar mutational load suggesting that the disease in dogs may also be immune responsive. In this study, the investigators will evaluate the safety and effectiveness of a novel targeted, immune therapy that aims to promote a powerful immune response against a specific gene mutation (V600E B-Raf) recently identified in up to 87% of dogs with UC. The investigators hypothesize that vaccine-induced anti-tumor immune responses will lead to tumor regression and that such favorable responses will correlate with the baseline mutational burden of the tumor. The investigators will use standard immunological methods and advanced genetic sequencing technology to study systemic and intra-tumoral immune responses to identify biomarkers that may predict immunological and clinical response in dogs.
My research interest is cancer genetics with an emphasis on clinically relevant questions that will improve our understanding of the cancer genetics of clinical phenotype and simultaneously improve patient care in oncology. I have extensive bench research experience in the fields of genome sequencing technology development, human genetic analysis through human genome sequencing and molecular assay development. My research benefits from the various innovations in genomic and genetic technologies that my group has developed.
In addition to breast cancer, women who carry a defective copy of the BRCA2 (Breast Cancer Susceptibility) gene live with an incredibly high risk for ovarian cancer. Alterations in the BRCA2 gene can be passed down from parent to child (hereditary mutation) or may arise spontaneously (somatic mutation) in ovarian tumors. The biological role of BRCA2 is to repair damage to the human genome. However, the specific details of how defects in BRCA2 lead to ovarian cancer remain to be defined. The foundation of our collaborative research effort is to elucidate the molecular and genetic wiring that underlie this lethal malignancy. By identifying key players and pathways that drive ovarian tumor growth and treatment resistance, we can expose vulnerabilities that will guide the development of targeted therapies, novel biomarkers, and improve outcomes for patients. One of the highlights of the past two decades of research into BRCA biology was the discovery that patients can be treated with PARP inhibitors, drugs that target a specific DNA repair pathway, resulting in dramatic killing of BRCA deficient tumors. Unfortunately, not all patients respond to PARP inhibitor therapy, and some patients eventually relapse, thus detailed knowledge of the molecular mechanisms that lead to tumor formation and treatment resistance are needed. Our goal in this team-based research effort is to understand how PARP inhibitors selectively target BRCA2 deficient ovarian tumors, identify the molecular routes to PARP inhibitor resistance, and leverage these findings to impact clinical decision rules.
When an individual is born with one mutated (or abnormal) copy of BRCA1 or BRCA2, there is a high chance that they will develop cancer. Drugs called PARP inhibitors have been developed to take advantage of DNA repair deficiency in BRCA related cancer, but they do not work in all patients, and resistance to the medications frequently develops. There is a pressing need to more deeply analyze primary tumors in BRCA1/2 mutation carriers to see how often there are “subclones” that have other types of primary resistance to PARP inhibitors and other therapies. This information will be critical to rationally design new strategies that will overcome a broad spectrum of resistance mechanisms. Due to a higher burden of DNA mutations in BRCA1/2 related tumors, there is significant excitement about the prospect of using immune therapies for these cancers. However, further research is needed to understand the baseline immune status of BRCA1/2 tumors and the pathways in which the immune system can be turned ‘on’ in these tumors. We propose a novel strategy to use inflammatory and immune responses that target both sensitive and resistant cells within a tumor.
To address these important objectives, we present two integrated aims that utilize our collective expertise in cancer genomics, DNA repair, tumor immunology, and mouse models of cancer. Consistent with the goals of the Team Science Convergence Award application, researchers from multiple schools, departments and divisions at the University of Pennsylvania will work together to maximize innovation and productivity.
The goal of this project is to provide women with BRCA2 mutations with a better option for reducing their risk of breast cancer while managing the menopause symptoms caused by removal of their ovaries. After ovaries are removed, BRCA2 carriers must balance management of menopause symptoms against high risk of primarily hormone-driven breast cancers, without much data about the long-term safety of hormone replacement. A new combination of bazedoxefine,a tamoxifen-like medication, and conjugated estrogen (BZA/CE or Duavee® ), has been extensively studied in postmenopausal women (without mutations) with established safety data . BZA/CE should reduce breast cancer risk without compromising quality of life for BRCA2 carriers by causing menopausal symptoms, bone loss or uterine problems. The randomized clinical trial compares BZA/CE to CE alone for 3 months in women carrying a BRCA2 mutation soon after ovary surgery. Their breast tissue will be examined to assess whether, as predicted, the BZA/CE has protective effects against breast cancer compared to the CE alone. After 3 months, the study is unblinded so those on CE can take a short course of progesterone. The exciting part of the project is all of the novel science that will be applied to assess the action of BZA/CE and CE on normal breast tissue in women with BRCA2 mutations. This has not been very well-studied, and is critical not only for breast cancer prevention but also for potential therapeutic implications for the cancers BRCA2 mutation carriers can develop.
Funded by 2018 Kay Yow Cancer Fund Final Four Research Award
Endometrial cancer (EC) is the most common gynecologic cancer in the developed world, and the 4th most common cancer in women in the United States, with over 60,000 diagnoses expected in 2017. While most women diagnosed with EC have a favorable prognosis following hysterectomy, a subset have poor outcome despite what is thought to be a “low risk” disease. Identification of factors that predict poor outcome have been elusive to date. With the expansion of the knowledge of the genetic basis of cancer, we and others have begun exploring “molecular” prognostic factors – the genetic signature of the cancer that may predict outcome. This proposal aims to study a large sample of women with EC, testing their cancer for its genetic signature, and correlating this signature with clinical outcome. Identification of the signature that predicts outcome will allow for a more refined approach to identification of women who would benefit from additional therapy following hysterectomy to improve survival. This will be done in a process that is able to be replicated in most hospital laboratories, allowing this project to be relevant and accessible in all communities in which women are diagnosed with this disease.
Nearly 1 million individuals in the United States have inherited mutations in the BRCA1 or BRCA2cancer susceptibility genes and have a very high risk for several cancers, including breast and ovarian cancer in women. Although clinical screening in individuals with known genetic risk can help identify cancers early when they are potentially more curable, this approach is imperfect. Therefore, there is an urgent need to identify ways to better detect and treat cancers in this high risk population. Like most cancers, those that arise in BRCA1/2 mutation carriers have an unstable genome.Manytypes of genomic instability are initiated by DNA breaks, particularly in BRCA1/2 carriers, as these genes are normally involved in DNA repair. Understanding how DNA breaks arise and are repaired is thus critical for understanding how cancer arises, and for developing therapies that specifically kill cancer cells or prevent their development.Our work indicates that when genomic DNA is transcribed into RNA, the RNAand DNA may get tangled, creating RNA-DNA hybrid molecules, or R-loops, that cause the DNA to be broken. BRCA1 and BRCA2 proteinshelp prevent R-loop formation. This raises the possibility that BRCA1 and BRCA2 prevent breast cancer development by regulating the formation of R-loops. In this proposal, we will explore what BRCA1 and BRCA2 do at R-loops, determine where R-loops form in cells without these genes and explore the possibility of using RNA-DNA hybrids as early, sensitive markers of cancer to improve detection and treatment.
Funded in partnership with the Buster and Kristen Posey Fund with support from Apple Gold Group
Despite numerous clinical trials for children with high grade glioma, including diffuse pontine glioma, either at initial diagnosis or recurrence, over the past 4 decades, there has been little improvement in patient outcome. In contrast, in the past few years major advances have been made in understanding the molecular underpinnings of these tumors. Specific, gene mutations in the genes encoding the histone H3.3 (H3F3A) and H3.1 (HIST1H3B, HIST1H3C) variants, along with BRAF V600E, mark distinct subgroups of disease in children and young adults. This proposal will combine our innovations in the clinic using the genetically recombinant poliovirus PVSRIPO with targeting technology aimed at these exploiting these mutations as targets.
In the currently accruing adult trials and the planned initial pediatric high grade glioma trial, PVSRIPO is administered by delivery into the tumor, via a surgical approach. In many pediatric glioma patients, diffuse infiltrating growth or location (e.g. diffuse intrinsic pontine gliomas; DIPG) precludes such intra-tumoral administration.
We plan to test a modified PVSRIPO technology for peripheral immunization with tumor-specific targets to create a viable alternative in pediatric brain tumors. We have recently developed robust technology to modify PVSRIPO for use as an immunization vector and have demonstrated PVSRIPO vectors do not require intratumoral administration and are able to generate tumor antigen-specific immune responses. These discoveries will enable us to develop virus based vaccination strategies for pediatric brain tumor patients where tumor-specific antigens are homogeneously expressed.
The human immune response can not only eliminate infections caused by viruses, bacteria and fungi, but can also kill cancer cells. Immunity is mediated by white blood cells. Among the different types of white blood cells, killer T cells can eliminate cancer cells, whereas regulatory T cells and some types of macrophages can block anti-cancer immunity and actually support cancer growth. The ability of killer T cells to eradicate cancer cells can be blocked by “immune checkpoint” proteins within the tumor microenvironment. Drugs have been developed to inhibit immune checkpoints (CTLA-4, PD-1 and PD-L1); thereby releasing the “brakes” on killer T cells to fight cancer. Using a combination of immune checkpoint inhibitors more than half of patients with widespread melanoma can experience long-term remission and possible cure.
Unfortunately, immune checkpoint inhibitors have been largely unsuccessful in patients with advanced prostate cancer. To better understand why they are not more effective, Dr. Subudhi’s team has evaluated the immune profile of primary and metastatic prostate cancers. They have found that the bone metastatic site is a highly immunosuppressive environment. This likely accounts for the poor clinical responses seen in patients with metastatic prostate cancer treated with a single agent immune checkpoint inhibitor. The overall goal of Dr. Subudhi’s clinical trials program is to improve survival in patients with advanced prostate cancer by enhancing T cell functions while eradicating the immunosuppressive cells within the cancer. Ultimately, his aim is to make immunotherapies in prostate cancer as effective as they are in melanoma.
Unlike childhood leukemia that has a 90% cure rate, outcomes for adult patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remain poor. With modern chemotherapy regimens, complete remission rates are 60-70%, yet long term cure rates remain dismal at 15-25%. Prognosis is even worse in older patients and/or those with high risk features, with remission rates of only ~35-50% and cure rates less than 10%. Efforts to improve both the remission rate and the durability of remission are paramount.
Dr. DiNardo’s team focuses on mutations in the genes IDH1 and IDH2, which occur in ~20% of patients with AML and occur more frequently in older patients. In her clinical trials, she has tested targeted drugs that inhibit these two mutated proteins (IDH1 and IDH2) and can lead to dramatic clinical responses. These novel drugs can be taken by mouth, are well-tolerated and promise to improve the survival of patients whose leukemic cells bear these mutations. The use of these drugs that can be taken by mouth, alone and in combination with other leukemia-directed therapies, will permit patients to be treated at home with less frequent trips to MD Anderson. She will carry out not just a single trial, but a program of multiple trials to have a major impact on the lives of patients whose cancers have IDH1 and ID2 mutations. Dr. DiNardo is also striving to make screening for multiple mutated genes the standard of care for patients with MDS and AML, which is not often performed in the community, in order to optimize treatment and accelerate best practices for older adult patients with AML.
