Steven Barthel, Ph.D.

The precision oncology approach to the treatment of cancer bases treatment decisions on the biology of an individual’s cancer, most often using genetic alterations or mutations to inform therapy.  This approach has been successful in a few cancer types, including lung cancer, melanoma, and chronic myelogenous leukemia where oral targeted therapies have led to both improved patient outcomes and fewer side effects compared to standard chemotherapy. However, this approach has not yet realized its full potential in these or other cancer types. In this proposal we plan to study new cancer-causing gene mutations involving the NTRK1, NTRK2 and NTRK3 genes, which are found in numerous types of cancer.  We have already demonstrated that tumor cells treated with targeted therapies against this gene family can kill cancer cells in the laboratory.  We have also observed early and dramatic tumor shrinkage in patients with different tumor types that share mutations in these NTRK genes. This proposal will focus on determining additional mutations of NTRK genes that may respond to therapy. The proposal will also study how cancer cells become resistant to targeted therapies and develop new laboratory models of NTRK+ cancer to develop new therapies for these cancers.

Je Lee, Ph.D.

Pancreatic cancer is one of the most deadly diseases in the U.S. It is hard to diagnose early, and it does not respond to treatments when discovered late. Therefore, new methods for early diagnosis and prevention are critical. Currently, our approach to finding cancer biomarkers relies on technologies that lack spatial or temporal resolution for discriminating individual cells and tumor regions. In fact, much of our analyses are based on average measurements from the mixed population of different cell types within the tumor tissue. This means that each biomarker has to be validated in multiple experimental and pre-clinical settings through very time-consuming and expensive processes, severely hampering our ability to discover diagnostic or therapeutic biomarkers. We developed a novel method to image and sequence DNA and RNA genome-wide without extracting them from the tissue, and the nucleic acid sequence is visualized directly under the microscope. Therefore, we combine positional features associated with cancer progression and molecular or genetic features associated with cancer clonal evolution. Our proposal will determine genetic sequences associated with each pixel of cancer tissue images to generate a map of genetic alteration and biomarkers as a function of the tissue landscape. If successful, our proposal could signal a new approach to discovering genetic biomarkers using specific architectural hallmarks of cancer, rather than average gene expression differences between heterogeneous tissues.

Luis Batista, Ph.D.

Funded by the Dick Vitale Gala with a gift from Derek and Christin Thompson in memory of Bryan Lindstrom

Bone marrow failure syndromes are a collection of disorders characterized by inadequate production of blood cell lineages from a common progenitor, the hematopoietic stem cell. Dyskeratosis congenita is an inherited bone marrow failure syndrome that comes to clinical attention during early childhood, and is associated with high rates of malignancy in children and young adults, with cancer being a major cause of death in patients. DNA sequencing efforts have established that dyskeratosis congenita has a clear genetic determinant, with patients carrying mutations in their DNA that affect the function of telomerase, a dedicated protein complex that is primarily responsible for maintaining the structure of our chromosomes.

Research regarding dyskeratosis congenita has been hampered by a lack of adequate models. In this proposal we are using genetically engineered human pluripotent stem cells to precisely determine the role that TERC, one of the main components of the telomerase complex, plays in bone marrow failure and cancer in children afflicted with dyskeratosis congenita.  Using our innovative model, we will understand the importance of TERC for stem cell regulation and blood development. Recently we developed the technology to differentiate these stem cells in a controlled, quantitative fashion, to become any particular blood cell type present in the circulatory system. This allows us to reproduce the clinical effect of this disease, in a tissue culture dish, and therefore precisely understand the disease progression in dyskeratosis congenita. Our goal is to help delineate novel treatment strategies against dyskeratosis congenita, a condition that currently has no cure.

Peter O’Dwyer, M.D. & Yuval Elhanati, Ph.D.

Funded in Collaboration With

Stand Up To Cancer (SU2C)

Pancreatic ductal adenocarcinoma (PDAC) is a common and increasing cause of cancer death in the U.S.A. While attempts to harness the immune system to fight cancer has been successful in the treatment of many cancers, these strategies have to date been ineffective in PDAC. PDAC tumors contain not only cancer cells but a dense layer of fibrous tissue, called stroma. The stroma interferes with the immune systems ability to attack PDAC both by releasing substances that inhibit the immune system and by acting as a physical barrier to immune cells reaching the cancer cells. We have recently shown that Vitamin D can act on PDAC tumors to prevent the stroma from releasing immune inhibitory substances and to facilitate immune cell entry into tumors, potentially setting the stage for a more effective immune attack on PDAC. In this proposal, the post-doc/clinical fellow will work closely with a team of physicians, cancer immunologists, and computational biophysicists will work together to improve the effectiveness of immunotherapy for PDAC. The post-doc/clinical fellow will contribute toward the completion of two tightly coupled aims: first, novel theoretical and experimental tools will be used to characterize the patient-specific immunological environment of PDAC tumors; second, the detailed understanding of the immune environment in PDAC tumors will be used to develop novel immunotherapy strategies that will be tested in a new clinical trial. The clinical trial will use a combination of conventional chemotherapy, a potent Vitamin D analogue, a drug that activates immune cells, and surgery, in an effort to improve the outcomes of patients with pancreas cancer. The Penn post-doc will be the critical individual who supplies operative tissue to the diverse collaborators in the project, and correlates the different genomic and immunologic studies with patient outcomes. As such they will gain knowledge and experience in molecular phenotyping of tumors, immunotherapy, and clinical trials.

Raul Rabadan, Ph.D., Junfei Zhao, Ph.D.

Funded in Collaboration With

Stand Up To Cancer (SU2C)

Tumors across different patients can be understood as independent evolutionary processes of clonal Darwinian evolution under distinct therapeutic evolutionary pressures. Different therapeutic strategies disrupt evolution in distinct ways allowing the inference of the order and co-mutation patterns specifically associated to these therapies. Inferring evolutionary patterns from large cross-sectional and longitudinal therapy specific cohorts will identify specific mechanisms of drug resistance, the genetic background of these mechanisms and will inform the dynamic model of the main routes of drug evasion.

First, using CAT(0) phylogenetic spaces, we will learn the statistics of phylogenetic processes associated specific drug mechanisms in breast cancer and melanoma. We conjecture that undisrupted evolutionary processes follow linear patterns and that specific therapies generate distinct branching patterns associated to number of alterations needed for relapse and effective size of the resistant population. Second, the highly branched processes associated to therapy allow to reconstruct the genetic alterations of ancestral clones allowing to order the genetic alterations. Combining cross-sectional information, one can elucidate the main routes of drug resistance, what alterations are selected under specific therapy and which is the mutational background in which they arise. As genomic data from clinical studies will be arriving we will generate first evolutionary models and integrate the results with the networks from dynamic modeling. By combining genomic data of longitudinal studies with state of the art network inference, we aim to uncover the main mechanisms of drug resistance and design combinatorial approaches.

Harlan Robbins, Ph.D. & Miriam Gutschow, Ph.D.

Funded in Collaboration With

Stand Up To Cancer (SU2C)

The last two decades have seen the development of increasingly effective cancer therapies that target different facets of transformed cells, including aberrant proliferation/survival, immune evasion, hyper-activated signaling pathways and dysregulated transcriptional programs. In a subset of cancers, including acute myeloid leukemia (AML) and non-small cell lung cancer with activating EGFR mutations, these therapies lead to dramatic clinical responses in a significant proportion of patients.

However, in the majority of AML and EGFR mutant lung cancer patients who respond to anti-cancer therapies, therapeutic relapse subsequently ensues, although often after a considerable interval, such that these responses do not lead to long-term cures. Often the relapsed tumors are infiltrated by adaptive immune cells (T cells). With the advances in immunotherapy, which utilize a patient’s own immune system to fight the cancer, it is possible to treat with immunotherapy after relapse. We are studying the T cell infiltrates before, during, and after relapse in both AML and NSCLC patients to determine if the response if the relapsed tumors have the characteristics of an immunogenic tum.

Kira Gritsman, M.D., Ph.D.

Acute myeloid leukemia (AML) is a devastating disease with poor survival. The standard treatments of chemotherapy and/or stem cell transplantation are not specific, and are toxic to blood cells, resulting in severe treatment-related complications for patients. Leukemias are composed of rapidly dividing “blast” cells, and the more rare “leukemic stem cells” (LSCs). These LSCs can lead to resistance and relapse, because they can evade chemotherapy. To achieve long-term remissions in AML and prevent relapse, we need to find more specific ways to kill LSCs.

The enzyme PI3 kinase (PI3K), which can modify proteins inside the cell, is more active in leukemic cells than in normal cells. However, PI3K is also important in normal blood cells. We identified a strategy to specifically kill leukemic cells by blocking specific components of PI3K called “isoforms”, which can sometimes substitute for each other in normal blood cells. We will determine whether this therapeutic strategy can also be used to kill LSCs.

Leukemic cells can also evade chemotherapy by hiding in their bone marrow microenvironment, the “niche”. Niche cells and leukemic cells “talk” to each other by sending signals back and forth, which can protect leukemic cells from chemotherapy. Cells need PI3K to process such signals. Inhibition of PI3K in niche cells could potentially kill leukemic cells by short-circuiting this crosstalk with the niche. We have found that PI3K in the niche cells is important for blood development. We will now examine whether inhibition of PI3K in the niche can compromise leukemic growth and progression.

 

 

Corinne Linardic, M.D., Ph.D.

Funded by the Apple Gold Group

Rhabdomyosarcoma (RMS) is the most common soft tissue cancer of childhood.  Because RMS has features of skeletal muscle, we and others have been trying to understand how muscle development pathways inside the tumor cells have gone awry.  This project will study the role of a protein called SFRP3, which although it takes part in normal muscle formation, is co-opted to support RMS tumor formation.  We aim to understand in more detail how SFRP3 works in RMS, and how to block it.  Our goal is to someday use SFRP3 blockade as a therapeutic intervention.

Hideho Okada, M.D., Ph.D.

Funded by the 2015 Wine Celebration Fund a Need, including donations raised by the Dick Vitale Gala and Bristol-Myers Squibb

Recent research revealed that malignant gliomas in children often have common gene mutations in a molecule named H3.3, which is a component of the human genome.  Approximately 30% of pediatric glioblastoma and 70% of diffuse intrinsic pontine glioma (DIPG) cases have the same mutation which causes a change in the H3.3 protein. The human immune system, such as T-lymphocytes (T-cells hereafter), do not normally react to normal proteins, but can recognize and attack cells that have abnormal proteins. Therefore, cancer-specific mutations can be suitable targets for cancer immunotherapy, such as cancer vaccines and adoptive T-cell transfer therapy (i.e., infusion of large number of T-cells). Indeed, immunotherapy using patients’ own T-cells that are engineered to recognize cancer cells have shown remarkable success in other cancers, such as acute lymphocytic leukemia in children. However, it is also important to ensure that those T-cells attack tumor cells but not normal cells. We recently found that the common mutation in H3.3 includes cytotoxic T cells which can kill glioma cells that have the mutation but not cells without the mutation.  We are proposing two lines of translational studies. First, we will isolate genes for the T cell receptor which allows the specific recognition of mutated glioma cells. This will lead to a near future development of adoptive transfer immunotherapy. Concurrently, we will design and conduct a pilot vaccine trial using synthetic peptide for the mutated part of H3.3 in children with H3.3-mutated DIPG or high-grade glioma.

Jeremy Reiter, M.D., Ph.D.

Funded by the 2015 Wine Celebration Fund a Need

More children die from brain tumors than any other type of cancer, and the most common type of brain tumor in children is medulloblastoma. Children with medulloblastoma are treated with surgery, radiation, and chemotherapy, and more than 50% of patients survive into adulthood. However, the treatments used for medulloblastoma lead to many long-term side effects, including growth defects, hormone abnormalities, and impaired intelligence. Like all cancers, medulloblastoma is caused by uncontrolled cell growth. Approximately one-third of medulloblastoma cancers arise when a particular signal that tells brain cells to grow, called Hedgehog, gets stuck in the “on” position. We are interested in uncovering exactly how Hedgehog signals tell medulloblastoma cells to grow. To do so, we are investigating how the Hedgehog pathway is activated, and how Hedgehog activation regulates the expression of other signals to influence cell growth. In particular, we are using existing drugs to understand whether block critical mediators of Hedgehog effects blocks the growth of medulloblastoma. Understanding how Hedgehog signals cause cancer may show us how to turn off these signals, and potentially, lead to new therapies for medulloblastoma.

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