The global burden of cancer, severe pathology bottlenecks in underserved regions, and evolving medical knowledge increase the need for inexpensive and rapid diagnostic approaches for point-of-care use. We developed a low-cost imaging module (D3), mountable onto standard smartphones, that exploits holography to detect and profile tumors using scant clinical samples. Cells are decorated with plastic beads coated with antibodies against various cancer markers. Recorded holograms (inherently noisy and undecipherable images) are transmitted wirelessly to a remote server via a secure, encrypted cloud service. Results are rapidly reconstructed and returned to the end user’s smartphone screen along with a diagnostic readout. Pilot testing of human biopsies demonstrated protein profiling capabilities comparable to gold standard methods and excellent diagnostic accuracies compared to expert pathology interpretation. To render the platform poised for global field testing, we propose to optimize D3 to achieve simultaneous, multiple marker testing along a spectrum of field conditions using scant samples. We will then inaugurate this next generation platform and pilot its global oncology reach by tackling a key unmet need – early breast cancer detection in Botswana. Testing for key markers in breast cancer specimens is universal practice in developed regions yet rarely performed elsewhere due to highly inadequate resources. Instead, empiric treatment with anti-estrogens occurs leading to over/under treatment and significant drug-drug interactions (e.g. reduced HIV medication levels). D3 could position itself as a key early detection tool in global regions, enabling judicious and personalized treatment and increased biological insight.
About 1 in 8 U.S. women will develop breast cancer over the course of her lifetime, and in the year of 2014, breast cancer has claimed the lives of approximately 40,000 women and men in the United States. Although initial remission can be achieved with chemo-treatments, the worry and fear of treatment resistance, recurrence, and death still have a deep impact on many breast cancer patients. It is recognized that cancer stem cells (CSCs), a long-lived, self-perpetuating cell population that can infinitely give rise to the bulk of a tumor as the “seed” of the cancer, account for cancer initiation, progression, chemoresistance, and recurrence. To date, treatment strategies designed to eliminate the genesis of the cancer (CSC) still remain a significant challenge. This project aims to identify critical cell components and their working mechanisms that are used to sustain the stemness of breast CSCs, and the identified mechanism will further be therapeutically targeted to direct CSCs to a differentiated cell (non-stem cell) fate, allowing breast tumors to become terminally dormant and sensitive towards chemotherapy. Our goal is to eradicate breast cancer in the next 10 years, and with the common stemness properties of CSCs between many cancer types, we believe that the applications generated from our research will continuingly contribute to overcoming the therapeutic hurdles of a broad spectrum of cancers and significantly benefit the cancer patient and the survivor community for decades.
Colorectal cancer is the second leading cause of cancer deaths in the United State, with African Americans having a significantly higher risk of developing colorectal cancer and of dying from colorectal cancer than do Caucasians. This study is based on the recent milestone publication from our team finding that 41% of colorectal cancers from African Americans are molecularly distinct from colorectal cancers from Caucasians, with African American colorectal cancers bearing mutations in certain genes that are never or rarely mutated in Caucasian colorectal cancers (dubbed: African American Colorectal Cancer, or AACC, genes). This proposal will examine whether AACC genes are similarly targeted for mutation in cancers from African Americans that live in different regions of the country; whether AACC gene mutations are associated with more aggressive colon cancer behavior; whether cancers with AACC gene mutations appear different under the microscope; whether AACC gene mutations show molecular footprints of exposures to environmental carcinogens; and whether mutations of AACC genes preferentially target genes that are inherited from African versus from Caucasian forebearers. We further will develop functional models for two AACC genes (EPHA6 and FLCN) that are mutated exclusively in African Americans and will test effects of these mutations on the ability of cancer cells to grow and to metastasize. We moreover will determine if the presence of these mutations turns on any signaling pathways whose activation would render these cancers sensitive to treatment with new types of anti-cancer drugs that are designed to target and shut down specific cancer-associated signaling pathways.
Acute lymphoblastic leukemia (ALL) is an aggressive cancer of the blood and a leading cause of disease-related death in children and adolescents. Cure rates of ALL have improved over the last decade thanks to innovative therapies, but it came at the cost of often severe toxicity associated with chemotherapy that can have long-lasting debilitating effects on children. The goal of our research is to move from the “sledgehammer” delivery of chemotherapy to “surgical precision” personalized ALL therapy, to minimize side effects and improve survival. We have recently discovered genetic factors (variations of our genetic make-up, DNA) that strongly influence the way thiopurine (an important anti-leukemic drug) is processed in patients, and we found that 80% of severe toxicity of this drug is due to genetic defects in two genes. Therefore, we reason that 1) patients should be tested for these DNA variations before ALL therapy starts, and 2) the genetic test results can be used to tailor chemotherapy for each patient to avoid toxicity, an approach also known as pharmacogenetics-based precision medicine. To achieve this goal, we have assembled an outstanding group of basic scientists and clinicians in 5 countries with diverse expertise, to preform comprehensive research in laboratory as well as clinical research in clinical trials of ALL. If funded, this work is likely to have immediate impact in the way we treat children and adults with ALL, demonstrating the importance genetics-guided precision medicine in cancer in general.
Rectal cancer affects 40,000 individuals in the US every year. The primary treatment is surgical resection when possible but a growing number of patients receive pre-operative chemo-radiation therapy before surgery to improve outcomes. In up to 30% of these patients, the tissue removed from the rectum after chemo-radiation is found to have no evidence of the original tumor. However, at present, the only accurate way to find out if the tumor responded completely to pre-operative chemo-radiation is to go through with surgery. There are no established biomarkers that can identify patients with complete response before surgery so that they may be potentially saved from a morbid operation. In previous work, we have shown that cancer mutations can be detected in blood plasma from advanced cancer patients. We have also shown that changes in the circulating levels of these mutations correlate with tumor burden. In this project, we are evaluating detection of cancer mutations in plasma from patients with rectal cancer as a potential biomarker. Our goal is to identify patients with rectal cancer whose tumors have completely receded after completing chemo-radiation before they under go surgery. These results will set the stage for prospective follow-up studies to enable biomarker-guided non-operative management of localized rectal cancers.
In spite of tremendous advances in the treatment of estrogen receptor-positive (ER+) breast cancer using therapies directed against the estrogen receptor (ER), patients frequently develop resistance to these therapies. These resistant tumors remain the most common cause of breast cancer death, yet mechanisms by which this resistance develops are poorly understood. Much more work is required to fully understand all of the clinically relevant resistance mechanisms in breast cancer patients treated with ER-directed therapies. Moreover, there is an urgent need to develop new therapies for patients who no longer respond to these therapies. The goal of this project is to improve our understanding of resistant ER+ breast cancer by using cutting-edge genomic technology to directly characterize tumor samples from patients who have developed resistant breast cancer, as well as systematic pre-clinical approaches in breast cancer cell lines. First, we will use next-generation sequencing technology to comprehensively characterize the genomic and molecular alterations from breast tumor samples obtained from 50 patients who have developed resistance to the drug fulvestrant, an FDA-approved therapy that directly targets the estrogen receptor. At the same time, we will conduct a systematic pre-clinical study in breast cancer cell lines to identify genes that might contribute to resistance to fulvestrant. Once completed, this work should help us understand how ER+ breast cancers develop resistance to ER-targeted therapies, as well as identify new targets and therapeutic strategies in resistant breast cancer.
Brain cancer is the leading cause of cancer-related death in children. Current therapies for medulloblastoma, the most common type of aggressive childhood brain cancer, cure 60-80% of patients from their disease, however, these treatments are non-specific, highly toxic, and impose devastating consequences on the developing child. Novel, rationally designed therapies informed by studying medulloblastoma in the laboratory and identifying the causes of this childhood cancer are desperately needed to improve patient outcome and quality of life for survivors and their families.
Studies outlined in this application aim to gain a better understanding of the genes responsible for a large subset of medulloblastoma patients whom are typically associated with an exceedingly poor clinical outcome. There are currently no effective therapies designed to specifically treat these high-risk patients and as such they are treated with standard protocols that carry with them considerable side-effects, effectively stealing any possibility of a normal ‘life after cancer’ for kids fortunate enough to survive.
Discoveries made using state-of-the-art technologies during my recent Post-Doctoral Fellowship revealed important new insight into the genes involved in these high-risk medulloblastoma patients. The most compelling evidence from my analyses implicated a new gene – KBTBD4 – a gene not previously implicated in childhood brain cancer, nor in any other cancer type. The experiments outlined in this application will directly evaluate the role of this novel, frequently altered gene (most commonly affected gene in high-risk patients) in medulloblastoma and establish its potential as a future target of therapeutic intervention in high-risk patients.
Lung cancer is the most common cause of cancer death in the US and worldwide. Because it has a five-year survival rate of only 18 percent, new therapeutic approaches are urgently needed. We propose to develop novel therapies by targeting the Wnt signaling pathway, which is involved in normal cell growth, but is also implicated in lung cancer development, progression and metastasis. Historically, Wnt signaling has been challenging to target directly, but epigenetic changes that chemically modify DNA or DNA packaging proteins, known as histones, can turn Wnt signaling on or off. In over 80% of lung cancers, the WIF1 protein that normally turns Wnt signaling off, is not produced. We showed that a drug which alters specific modifications to histone 3 restores the production of WIF1, shuts down Wnt expression and induces lung cancer cell death. To advance our observations from bench to bedside, we will 1) determine how specific histone modifications and changes to WIF1 production and Wnt signaling correlate with the disease and its clinical outcomes; 2) analyze the biochemical mechanisms that alter histone modifications to suppress Wnt signaling; and 3) test the effectiveness of two experimental drugs that alter histone modifications to inhibit the tumorigenesis and progression of human lung cancer transplants in mouse models. Successful completion of these studies are expected to unravel important epigenetic pathways that promote Wnt signaling to induce lung cancer, and to identify new drug targets that will suppress Wnt signaling and dramatically improve the outcomes for lung cancer patients.
The advent of molecular biology and molecular profiling in clinical medicine has transformed our understanding of childhood leukemia. As a result, we are now empowered to shift away from the classification of hematologic malignancy based on microscopic appearance towards a new paradigm of diagnosis and treatment focused on specific molecular mechanisms of pathogenesis, or alterations detected in both leukemia cells and cells representing an individual’s heritable constitution. The heritable, constitutional or germ-line contribution to the development of childhood leukemia is a phenomenon increasingly recognized in childhood cancer. Studies to date have revealed the constitutional basis for cancers in subtypes of leukemia, however there is a clear missing heritability fraction given a high frequency of families without an identifiable genetic etiology. Given a lack of awareness and an incomplete germline evaluation, pediatric oncologists are unable to take avail of complete information pertaining to a child’s predisposition to developing leukemia when planning therapeutics and guiding. Knowledge of germ line alterations may direct patient care, and enable genetic counseling for patients and their families. My research focuses on identifying the heritable underpinnings of childhood leukemia.
Funded by the Dick Vitale Gala in honor of Leah Still
Neuroblastoma, an embryonal tumor that arises in the peripheral sympathetic nervous system (PSNS), accounts for ~10% of cancer-related deaths in childhood. About half of all patients, especially those over 18 months of age with amplified copies of the MYCN oncogene, present with evidence of widespread metastasis at diagnosis and have a very high risk of treatment failure and death despite receiving greatly intensified chemotherapy. Attempts to improve the treatment of metastatic neuroblastoma have been slowed by the lack of a full understanding of the multistep cellular and molecular pathogenesis of this complex tumor. Recently, I developed the first zebrafish model of neuroblastoma metastasis by overexpressing two oncogenes, human MYCN, which is amplified in 20% of neuroblastoma cases, and mutationally activated SHP2, which is the second most frequently mutated gene in high-risk neuroblastoma. This transgenic model affords unique opportunities to study the molecular basis of neuroblastoma metastasis in vivo, and to identify novel genes and pathways that cooperate with MYCN and activated SHP2 to promote this usually fatal stage of disease development. This research approach is expected to reveal novel molecular targets that can be exploited therapeutically. To achieve this goal, I propose to establish reliable in vivo zebrafish models of the aberrant genes and pathways that contribute to neuroblastoma metastasis. In the near future, these models will be used to screen for effective small molecule inhibitors that block specific steps in metastasis with only minimal toxicity to normal tissues, and thus would be assigned high priority as candidate therapeutic agents.
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