Miriam Cremer, MD

Cleveland Clinic Women’s Health Institute

CERVICAL CANCER

Pilot Award

Feasibility of Moving to Primary HPV Testing vs Co-Testing for Cervical Cancer Screening at Cleveland Clinic

Co-testing with cytology and HPV assays is the most common modality of cervical cancer screening in the United States, but current guidelines recommend transitioning to primary HPV screening. This study will address barriers to this transition, principally determining if false negative HPV tests in patients with high-grade precancers are due to the presence of non-oncogenic HPV types, rather than faulty screening. We will also evaluate readiness for this transition among key stakeholders in the Cleveland Clinic, a large and influential health system that has the potential to pioneer this important transition in cervical cancer prevention.

IN OTHER WORDS

The most common cervical cancer screening method in the US is co-testing (combining Pap and HPV testing), but guidelines now recommend transitioning to primary HPV screening. This study will address barriers to this transition, particularly if false negative HPV tests in patients are due to the presence of non-oncogenic HPV types. We will also evaluate perceptions of this transition among stakeholders in the Cleveland Clinic.

Robert DeBernardo, MD

Cleveland Clinic Women’s Health Institute

OVARIAN CANCER

Pilot Award

Improving Advanced Ovarian Cancer Outcomes with Translational Studies of HIPEC

Epithelial ovarian cancer (EOC) is a leading cause of cancer death in women, often diagnosed at an advanced stage once the cancer has spread throughout the abdomen. Hyperthermic intraperitoneal chemotherapy (HIPEC) has recently emerged as a clinical regimen that prolongs overall survival for patients with advanced EOC. Despite its proven clinical benefit, how HIPEC extends patients’ lives remains poorly understood. Through our initial research funded by VeloSano, we performed a single-cell RNAseq analysis of tumors pre- and post-HIPEC in patients with EOC. We discovered significant changes in the immune related pathways in patient tumors, specifically an increase in B Cell activity indicative of activation of a “memory” immune response. We therefore hypothesize that hyperthermic conditions sensitize EOC to chemotherapy agents through immune modulation. We propose two Specific Aims. Aim 1 will test the role of immune B cells in the efficacy of heated cisplatin. Aim 2 will test whether the efficacy of HIPEC is dependent on DNA damaging therapeutics. The goal of the study is to identify the immune pathways that HIPEC disrupts in order to translate these findings into adjunct therapies for the clinical benefit of HIPEC in patients with advanced EOC. This information will provide a basis for targeted drug design and development of cancer therapeutics.

IN OTHER WORDS

The most common cervical cancer screening method in the US is co-testing (combining Pap and HPV testing), but guidelines now recommend transitioning to primary HPV screening. This study will address barriers to this transition, particularly if false negative HPV tests in patients are due to the presence of non-oncogenic HPV types. We will also evaluate perceptions of this transition among stakeholders in the Cleveland Clinic.

Zihua Gong, MD

Cleveland Clinic Lerner Research Institute

OVARIAN CANCER

Pilot Award

Identification of a Novel Mechanism of Autophagy Inhibitor in Ovarian Cancer

Ovarian cancer is one of the most malignant gynecological tumors, with a high mortality rate owing to tumor recurrence after anticancer therapies. Although patients initially respond to therapies, a majority has disease that goes on to become resistant to all available treatments. Thus, the need is great to find new cures and effective therapeutic strategies for ovarian cancers. Autophagy is a cellular process implicated in response to multiple environmental stresses. It has been reported that autophagy is induced in ovarian cancer cells exposed to platinum chemotherapy as a way for undamaged tumor cells to escape death and survive. Thus, if autophagy is suppressed, tumor cells should become sensitive to treatment and die. Therefore, autophagy inhibition could be a strategy to increase ovarian cancer cell death and improve patient survival. A protein called RUNX3 suppresses tumor development and growth. We have found that RUNX3 might be a mediator that links autophagy inhibition to tumor cell death in ovarian cancer. Moreover, we propose to test a combination treatment (autophagy inhibition with chemotherapy) that offers the possibility to chemosensitize resistant ovarian cancer to conventional treatment. In conclusion, the project will provide necessary data to begin to determine whether autophagy inhibition combined with standard anticancer treatment may overcome the limits of current therapies and improve survival of those with ovarian cancer.

IN OTHER WORDS

This project investigates a previously unrecognized mechanism that underlies autophagy inhibition upregulates tumor suppressor RUNX3-induced tumor cell death and may be an important new approach to combine with conventional chemotherapy for ovarian cancer.

Hrishikesh Mehta

Cleveland Clinic Lerner Research Institute

BLOOD CANCER

Pediatric Pilot Award

Chemoprevention of Pediatric Leukemia Predisposition Syndromes Through Nonsense Suppression

Inherited bone marrow failure syndromes (IBMFS) constitute leukemia predisposition syndromes with a high rate of transformation to acute myeloid leukemia (AML). In children, AML has a 5 year survival rate of ~65%, but the prognosis of AML associated with IBMFS is poorer. Severe congenital neutropenia (SCN) and Shwachman Diamond Syndrome (SDS) are IBMFS with loss of neutrophil production. Over the years better disease management has led to increased survival, however development of AML is now the primary risk factor for death. The poor prognosis of AML makes it imperative to find novel treatment options that can prevent AML in vulnerable populations. I propose a novel approach to target both diseases prior to development of AML by taking advantage of a common factor in both diseases. I propose that suppressing the effect of nonsense mutations can be used to prevent AML. In SCN the nonsense mutations are acquired in the gene encoding the granulocyte colony stimulating factor receptor (CSF3R), while in SDS nonsense mutations make up majority of the germline mutations found in the Shwachman-Bodian-Diamond syndrome gene (SBDS). The result of these nonsense mutations are formation of truncated proteins that result in a pre-leukemic state. I propose that the nonsense mutations can be targeted using a nonsense suppression drug called Ataluren, which allows expression of the full-length neomorphic protein, instead of the truncated protein. Approved in Europe for the amelioration of Duchenne muscular dystrophy, Ataluren has not been evaluated in other conditions.

IN OTHER WORDS

Nonsense mutations result in truncated proteins that promote a pre-leukemic state in some children. Using a small molecule approach to manipulate the cellular protein making machinery to skip the nonsense mutations will promote normal full length protein. This approach will not only prevent development of cancer and treat the underlying disease.

Neetu Gupta, PhD

Cleveland Clinic Lerner Research Institute

LYMPHOMA

Pediatric Pilot Award

Chemoprevention of Pediatric Leukemia Predisposition Syndromes Through Nonsense Suppression

Cellular immunotherapy has revolutionized cancer treatment by harnessing the patients’ own immune system and redirecting it to kill cancer cells. One of the most promising areas of this work involves engineering the patient’s healthy T lymphocytes to display a Chimeric Antigen Receptor (CAR) on the cell surface. CAR T-cells act as “living drugs” and have shown outstanding success in patients with relapsed B cell lymphomas. However, the benefit of this therapy is not durable, and a majority of the patients suffer from toxicities associated with this treatment, including high fever, hypotension, respiratory distress, seizures and memory loss. These toxicities need to be carefully monitored and managed by clinicians to reduce morbidity and mortality. Therefore, there is an unmet clinical need to identify biomarkers that can predict toxicity and response to therapy, prior to initiation of therapy, as well as biomarkers that may be used to monitor patients for toxicity soon after therapy is initiated. These biomarkers will aid in personalizing management of patients by enabling more informed clinical decision making. Metabolites are key biochemical regulators of cellular processes; hence the metabolic “signature” of a patient is a unique identity that contains information about disease heterogeneity and drug response. We propose to develop a metabolomics- and statistics-based method to identify metabolic biomarkers of response and toxicity to CD19-directed CAR T-cell therapy. This technology will enable the development of clinical tools for oncologists to better predict, monitor, manage and mitigate toxicities, as well as researchers to improve the benefit of cellular immunotherapies.

IN OTHER WORDS

In this project, we propose to develop an unbiased metabolomics- and statistics-based approach to identify metabolic biomarkers associated with response and toxicity to novel cellular immunotherapies. This technology will enable clinicians to better predict, monitor, manage and mitigate toxicities, and researchers to improve patient response.

Babal Jha, PhD

Cleveland Clinic Taussig Cancer Institute

BLOOD CANCER

Joanne and Margaret Cohen Families VeloSano Pilot Award in memory of Rosalie, Morton & Carl Cohen

Oligoadenylate Synthetases, a Novel Therapeutic Target in Myeloid Neoplasms

The multistep mechanism of neoplastic evolution and cancer progressions are, in part, due to the defects in one or more pathways involving responses to, or repair of, damaged DNA and base excision repair pathways. Poly(ADP-ribose) modification of proteins is a major post-translational process that fundamentally impacts the DNA damage response with profound effects on cancer cell survival. 2’, 5’-oligoadenylate synthetases, an important component of intrinsic cellular antiviral innate immunity, are overexpressed in most of leukemic cells that are resistant to the therapy that works via DNA damage. Our analysis of publicly available database (http://www.cbioportal.org) showed that a group of MDS patients (15%) have 10 fold higher mRNA expression of OAS compared to normal, and the survival of these patients are way inferior when compared to low OAS expressing patients. The proposed research will lead to elucidation of one of the fundamental cellular processes in cancer cells that controls the cellular response to DNA damage in therapeutic resistance. The proposed project has far-reaching implications and significant intellectual merit. It is expected to lead to elucidation of a completely unexplored yet fundamental process that controls the DDR, with possible therapeutic implications for MDS and AML.

IN OTHER WORDS

This proposal will result in the development of a novel therapeutic approach for relapse and refractory Leukemia.

Adrian Lesmana, MD

Cleveland Clinic Children’s / Pediatric Institute

ALL CHILDHOOD CANCERS

Pediatric Pilot Award

Investigation of Childhood Cancer Predisposition Syndrome

The application of next generation sequencing has expanded our knowledge in the field of hereditary cancer predisposition. Multiple studies demonstrated that approximately 10-18% of all cancers are attributed to germline mutations due to cancer predisposition syndromes. However, a large proportion of pediatric-onset familial cancers remains without a known genetic cause. The primary goal of this study is to establish a clinical registry of systematically collected and validated clinical data from individuals with familial cancer and store their biological materials for genetic studies. We propose to use high throughput sequencing technology, including whole exome and/or whole genome and RNA sequencing, to identify novel genes predisposing to pediatric-onset cancer predisposition syndromes and to identify novel genes and/or genetic variants that influence clinical presentation (disease severity) in individuals with known cancer predisposition syndromes.
Identifying the faulty genes responsible for tumor formation in cancer-prone families makes it possible to offer genetic counseling and testing for at-risk family members, provide information about recurrence risk and inform clinical management through the institution of surveillance aimed at early cancer detection. If an identified genetic variant is determined to dysregulate pathways which would further compromise genetic integrity upon exposure to certain chemotherapeutic agents or radiation, then treatment could potentially be modified to mitigate excess toxicity or the risk for second therapy-induced neoplasms. Finally, the information gained will help us to better understand the pathways driving tumor formation and enable development of novel therapies.

IN OTHER WORDS

The goal of this study is to establish a Data Registry linked to a Biorepository of biological samples to facilitate genomic investigations of familial cancer.

Richard Padgett, PhD

Cleveland Clinic Lerner Research Institute

LEUKEMIA/BLOOD CANCER

Matthew and Stacey Litzler VeloSano Pilot Award

Myeloid neoplasms as a Global Spliceopathy: Implications for Molecular and Immune Pathogenesis

A number of diseases of the bone marrow, known collectively as myeloid neoplasms, cause losses of one or more type of blood cells and often progress to leukemia. These are mainly caused by the growth of clones of mutant cells in the bone marrow. Most of these diseases are difficult to treat and current therapies do not produce lasting remission so the identification of new targets is needed. Of the common mutations seen in these clones, over 60% affect genes that encode proteins involved in processing mRNAs in the nucleus by splicing. We have analyzed large collections of bone marrow samples from patients and healthy individuals to identify the molecular effects of these mutations. We identified hundreds of potentially useful targets in our computer analysis. Now we need to identify he useful ones by biochemical and further computational methods. First, we want to make sure the mis-processed RNAs are made in cells we can study and are not found in any normal tissues in the body. Then we need to show that they can actually make novel proteins. Then we need to show that these proteins can be correctly presented to the immune system. In the end, we will have lists of validated novel proteins that can serve as diagnostic markers and, we hope, as new targets for immunotherapies to suppress or eliminate these diseased clones in the bone marrow.

IN OTHER WORDS

We have found many potential new proteins made only in leukemic bone marrow cells. We need to find which ones might be useful for diagnosis and/or treatment. We plan to produce ranked lists of candidates that have the best chances of being useful.

Ruth Keri, PhD

Cleveland Clinic Lerner Research Institute

BREAST CANCER

Sandy’s Domestiques VeloSano Pilot Award

SMC2 Regulation of Chromosomal Instability in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is a highly aggressive disease that disproportionately affects young and African American women. Women diagnosed with TNBC are treated with chemotherapy and they frequently develop metastatic disease within 2-3 years. Once this occurs, there are very limited treatment options and the prognosis for these patients is poor. A recent expert analysis of breast cancer needs indicated that identifying new therapies for TNBC was a top 10 priority. In this regard, we have recently identified a protein, called SMC2 that we anticipate controls the processes by which TNBC cells become deadly. We found that tumors that have more SMC2 tend to be more malignant. We also found that TNBC cells need SMC2 to continue to grow. In this proposal we will discover how SMC2 controls TNBC growth. We hypothesize that SMC2 governs the way DNA is maintained in tumor cells as they are growing. We also propose that SMC2 controls the activity of genes that drive metastatic and drug-resistant features of TNBC cells, particularly resistance to chemotherapies. This VeloSano project will address both of these questions using state-of-the-art microscopy and genomic analyses of the cells. Lastly, we will ensure the clinical relevance of the project by testing our findings in tumor samples from patients with TNBC. If we find that SMC2 orchestrates TNBC biology, developing therapies that inhibit its function should be straightforward because it has a chemical property commonly targeted with new drugs. Such drugs may ultimately improve patient outcomes from this disease.

IN OTHER WORDS

This project aims to develop a better understanding of what drives triple negative breast cancer (TNBC) so that we can design effective therapies for this disease. We will investigate whether SMC2 causes TNBC to acquire changes in their DNA that make them more malignant and difficult to treat. This may reveal that SMC2 is a good target for developing a new therapy for TNBC.

Sarah Vij, MD

Cleveland Clinic Glickman Urological & Kidney Institute

MANY CANCER VARIETIES

Harry H. Esbenshade VeloSano Pilot Award

Fertility Potential Preservation in Boys Facing Infertility-Causing Diseases or Treatment Regimens with Testicular Tissue Freezing

Currently, no fertility preservation options are available for pre-pubertal boys who are not yet producing sperm. However, experimental techniques are currently being developed to provide future alternatives for patients that preserve their testicular tissue/cells. In order to take advantage of these and future technologies, patients must harvest and preserve their testicular tissue prior to disease or treatment associated with infertility. This study will harvest testicular tissue from eligible patients prior to undergoing therapy that will impact future fertility. Separate portions of the tissue will be banked for future research use and cryopreserved and maintained for participating patients as a resource for future elective procedures to attempt fertility restoration.

IN OTHER WORDS

Pre-pubescent boys undergoing cancer treatments do not presently have any fertility preservation techniques or therapies available. This study aims to harvest testicular tissue prior to gonadotoxic therapies for future utilization and research regarding future options for fatherhood. Additionally, this study will determine if undergoing testicular tissue cryopreservation reduces distress during and after cancer treatment.

Li Wang

Cleveland Clinic Taussig Cancer Institute

BREAST CANCER

Pilot Award

Examine the Role of VISTA in Regulating Anti-Tumor Immunity in Breast Cancer

Triple-negative breast cancer (TNBC) is a challenging disease with high rate of relapse and mortality following chemotherapy. While FDA has approved PD-L1/PD-1 inhibitors for TNBC treatment, the overall low response rate warrants effort to target new non-redundant immune checkpoint receptors (ICR). The V domain Immunoglobulin Suppressor of T cell activation (VISTA), first discovered by this study PI, Lily Wang, is a novel ICR that critically controls anti-tumor immunity and is a promising target for treating diseases resistant to PD-1 inhibitors. However, the immuno-regulatory mechanisms of VISTA in multiple immune cell lineages remain incompletely understood, which hampers the proper development of VISTA-targeting reagents as well as the identification of early biomarkers that could predict response.
This proposal focuses on defining the novel mechanisms by which VISTA regulates immunosuppressive myeloid cells. Our overall hypothesis is that VISTA promotes the differentiation and functions of tumor-associated MDSCs, which in turn impairs anti-tumor adaptive immunity and results in therapeutic resistance in TNBCs. We will test our hypothesis by first generating and characterizing novel GEMM breast cancer models where VISTA is specifically deleted in myeloid cells (Aim 1). We will further investigate the expression of VISTA in human TNBCs and determine how VISTA expression pattern is associated with the tumor transcriptomic profiles and clinical outcomes (Aim 2). We expect that these studies will establish VISTA as a causal factor for resistance and recurrence in TNBCs and lay the foundation for developing and testing VISTA inhibitors for improving breast cancer immunotherapy.

IN OTHER WORDS

Triple negative breast cancer (TNBC) is associated with high rate of relapse and mortality and shows overall low response rate to immunotherapies. These unmet clinical needs warrant efforts to identify new therapeutic targets. This project aims to define the mechanisms and prognostic roles of a novel immune checkpoint protein VISTA in mediating immunosuppression in breast cancer. Our results will lay the foundation for developing and testing VISTA inhibitors for improving breast cancer immunotherapy.

Jianjun Zhao, PhD

Cleveland Clinic Lerner Research Institute

MULTIPLE MYELOMA

Marc Harrison Impact Award

pERP1 as a Novel Therapeutic Target for Multiple Myeloma

Multiple myeloma (MM) is an incurable and heterogeneous plasma cell malignancy. Even though with current drug development including antibody drug such as daratumumab targeting CD38 in clinic, MM patients will finally develop drug resistance. Novel targeted therapy is urgently needed to overcome the multiple drug resistance. The aim of this proposal is to define the potential of pERP1 as a novel therapeutic target for MM. pERP1 is a helper for immunoglobulin assembling and secretion and specifically highly expressed in MM cells. We also found pERP1 was highly expressed on the surface of MM cell lines and the plasma cells from MM patients compared with plasma cells from donor. We hypotheses that blocking the function of pERP1 positive plasma cells in bone marrow using neutralization antibody may have therapeutic benefit MM patients. Since the need for novel and targeted therapy to overcome the drug resistance of end stage MM patients, this study is timely and translational, and potentially leads to better understanding of future treatment of this hematological malignancy.

IN OTHER WORDS

Increasing our understanding of the pathogenesis of hematopoietic malignancies will ultimately facilitate the translational research towards the discovery and development of novel therapy for patients. Our project aims to determine the potential use of pERP1, an immunoglobulin chaperone highly expressed in plasma cells, as a novel MM therapeutic target. If validated, this will be an important advancement in the treatment of MM. Furthermore, optimization of a monoclonal antibody to accurately neutralized the surface expression of pERP1 in patients will be extremely helpful in a clinical setting if pERP1 is validated as a therapeutic target for MM.

Jennifer Yu, MD, PhD

Cleveland Clinic Taussig Cancer Institute

BRAIN CANCER

Béla Szigethy VeloSano Pilot Award in memory of Maria Szigethy

Hypoxia-Regulated IncRNA in Glioblastoma Progression

Glioblastoma is an incurable primary brain tumor that is characterized by regions of hypoxia and marked resistance to radiation. Glioma cancer stem cells are a highly malignant subpopulation of cells that are highly resistant to standard treatments. These cancer stem cells are frequently located in hypoxic areas, making them more even difficult to kill with radiation. Cancer stem cells therefore play an important role in disease recurrence. Long non-coding RNAs (lncRNAs) have recently been found to be dysregulated in cancer. LncRNAs have multiple functions including regulation of gene expression. We have found that the lncRNA Lucat1 is an important regulator of glioma cancer stem cell response to hypoxia. Lucat1 is frequently overexpressed in glioblastoma and is associated with poor prognosis. Our data support that Lucat1 is induced by hypoxia and reinforces hypoxia signaling. In this study, we propose to study how Lucat1 regulates glioma cancer stem cell response to hypoxia and test inhibitors of Lucat1. If successful, our findings will provide a new therapeutic approach for targeting glioma cancer stem cells in hypoxia to improve glioblastoma treatment. This treatment strategy may be extended to other cancers including smoking-associated lung cancer and renal cell cancer that express high levels of Lucat1.

IN OTHER WORDS

Glioblastoma is an incurable brain tumor. Our studies will identify a vulnerability of the most aggressive cancer cells and offer a novel targeting strategy. These studies are expected to provide new treatments for patients with glioblastoma.

Anjali Advani, MD

Cleveland Clinic Taussig Cancer Institute

LYMPHOBLASTIC LEUKEMIA

Excellence in Leukemia Research Impact Award

Novel Therapies in Acute Lymphoblastic Leukemia

Our research has focused on novel therapies for patients with acute lymphoblastic leukemia (ALL). The prognosis of older adults (defined as > 65 years of age) remains poor (10% overall survival at 5 years). Therefore, new strategies are desperately needed. The majority of ALLs (80%) are of the B-cell subtype, and the marker CD19, sits on the surface of B-ALLs, making it an attractive target. Blinatumomab is an anti-CD19 antibody that binds to B-ALL cells and also activates the immune system through “engaging” T-cells. We have designed a trial treating patients with blinatumomab followed by low dose chemotherapy. The outcomes of this trial have been impressive with a 66% response rate and excellent 1 year outcomes despite patients with poor risk disease. For patients with relapsed/ refractory (R/R) ALL (where a patient’s leukemia does not respond to treatment or comes back), the outcomes are poor. Although T-ALL is less common than B-ALL (only 20% of ALLs), treatment for R/R disease has lagged behind. Recently, data has demonstrated that the enzyme AKR1C3 is overexpressed preferentially in T-ALL. We have developed a clinical trial (SWOG 1905) evaluating a novel drug, OBI-3424 in R/R T-ALL. This chemotherapy drug specifically requires AKR1C3 to be metabolized, and should preferentially kill T-ALL cells. We are collaborating with laboratory investigators to evaluate AKR1C3 expression and other biology to see if this predicts response.

IN OTHER WORDS

ALL is a difficult disease to treat. Our work is evaluating targeted therapies in B and T ALL with the hopes of improving clinical outcomes. We are also collaborating with laboratory investigators to identify other therapeutic targets as well as mechanisms of resistance.

Charis Eng, MD, PhD

Cleveland Clinic Lerner Research Institute

BREAST CANCER, THYROID CANCER

Pilot Award

Genome-Wide Cell-Free DNA Fragmentation as a Biomarker of Cancer Risk in Patients with Germine PTEN Mutations

Inborn errors within our genetic material, referred to as “germline mutations,” are major contributors to various diseases. Germline mutations play a major role in ~10% of all cancers resulting in 12 million living with genetic cancers in the US. Inherited cancers usually arise at unexpectedly younger ages. Therefore, identifying causative germline mutations as early as possible can flag carriers as “high-risk” so that proactive medical care can be practiced.
The big question: If you knew you or your loved one had 85% lifetime risk of breast cancer—a risk >6 times than for most women—what would you do?
Actress and humanitarian Angelina Jolie chose preventive surgeries to remove her breasts and ovaries. Her decision came after discovering she has a germline mutation that put her at notably higher risk of breast and ovarian cancers.
However, the challenge is that not everyone who inherits a cancer-causing mutation will necessarily get cancer and who precisely will get cancer is unknown. Yet, all mutation carriers, like Jolie, are flagged “high-risk”. This results in lifelong medical tests and surgeries that may have been unnecessary if we knew with 100% certainty who will get cancer.
Here, we study whether a specific form of blood DNA can help us tell the difference between “high-risk” individuals who will develop cancer versus those who will not. This has never been performed before for inherited cancers. If successful, it will be a groundbreaking discovery that can revolutionize how we think about cancer risks and how to focus on effective prevention at the individual level.

IN OTHER WORDS

Patients with PTEN hamartoma tumor syndrome are born with a very high (but not 100%) risk of cancer. However, while some get cancer, others never get cancer during their lifetime. We will study whether a specific form of DNA in the blood can help us tell the difference between the two.

Dennis Lal, PhD

Cleveland Clinic Lerner Research Institute

BRAIN CANCER

Pilot Award

Genetics of Low-Grade Neuroepithelial Tumors

Low-grade neuroepithelial tumors (LGNTs) are slow-growing brain tumors mainly seen in children and young adults. Due to their typical location within the frontal and temporal lobes, LGNTs almost always present with seizures. Following surgical resection, 10-year progression-free survival exceeds 85% in cases where complete resection is successful but drops below 50% in subjects with a radiologically visible residual tumor. For patients with tumors located in critical brain structures where total resection is not possible, adjuvant therapy often results in unsatisfactory tumor control and long-term morbidity. It is not well understood which patients require adjuvant therapies and why some LGNTs undergo malignant transformations. No comprehensive genetic screen has been performed for LGNTs, and as a result, the etiology of LGNTs is elusive in 50% of tumors. It remains unknown whether tumors with mutations in known cancer driver genes have additional co-occurring modifier mutations that correlate with tumor type, brain region, and malignancy. We have generated the largest and most comprehensive genomic dataset of LGNTs to date through external funds. Analyzing this world-wide uniquely comprehensive LGNT genomic dataset of 403 samples, combined with publicly available datasets, will enable us to identify new LGNT genes, understand the role of genetic modifiers, and group LGNTs into genetically-defined subtypes based on mutational signatures. Our studies will provide novel biological insights into the genetic etiology and risk of LGNTs. Our genetics-based stratification will allow for the development of novel gene-based diagnostic strategies and therapeutic alternatives to surgery for patients with LGNTs.

IN OTHER WORDS

Low-grade neuroepithelial tumors (LGNTs) are brain tumors mainly seen in children and young adults. This project will perform the globally most comprehensive genetic screen for LGNTs. The results of this study will improve patient management and enable the development of novel gene-based diagnostic strategies for LGNTs.

Justin Lathia, PhD

Cleveland Clinic Lerner Research Institute

BRAIN CANCER

Stewart A. Kohl VeloSano Pilot Award in memory of Philip H. Kohl

Metabolic and Epigenetic Effects of Mitochondrial Transfer in Glioblastoma

Glioblastoma (GBM) is the most common and aggressive cancer that originates in the brain, and GBM remains deadly despite treatments including surgical removal, chemotherapy and radiation. While new treatment approaches (such as activation of the immune system to fight cancer) have been successful in other cancers, these strategies have not been successful in GBM. One major limitation to GBM treatment is interactions between tumor cells and surrounding non-cancerous cells, which aid cancer growth and resistance to therapies. Understanding these communication pathways is essential for preventing the non-cancerous cells from supporting the tumor and important for the development of effective new treatments. We found that one route by which non-cancerous brain cells help GBM is by donating their mitochondria to tumor cells. Mitochondria are cellular compartments that specialize in producing energy and also affect the overall biology of cells. Our preliminary results demonstrate that mitochondria donated to GBM cells change GBM cell metabolism and help them grow faster. Our objective is to investigate how these mitochondria can lead to treatment resistance and GBM growth by changing the way genes are regulated, in addition to impacting the energy use of tumor cells. To test this, we will investigate the genetic regulation of GBM cells that have received donor brain mitochondria. We will also test the effect of drugs that we have found to stop mitochondrial transfer on GBM growth in pre-clinical models. Ultimately, these studies will define a new way through which cells communicate and identify new treatment approaches for GBM.

IN OTHER WORDS

Glioblastoma is an incurable brain tumor, which becomes resistant to available treatment strategies by interacting with its surrounding microenvironment. We will explore a new communication mechanism between glioblastoma and surrounding cells in the brain facilitated by transfer of mitochondria. By investigating the triggers, impact and pharmacological inhibition of mitochondria uptake by glioblastoma cells, this project will enable the development of better treatments for this deadly disease.

Principal Investigator – Nathan Mesko, MD

Co-Investigator – Lukas Nystrom, MD

Cleveland Clinic Orthopaedic & Rheumatologic Institute

SARCOMA

Brian and Diana Taussig VeloSano Pilot Award in honor of Amanda Maggiotto

Tissue Perfusion and Complications in Soft Tissue Sarcoma Surgery

Soft tissue sarcoma is an often aggressive cancer commonly affecting the arms or legs. Most sarcomas are treated with a combination of radiation therapy and surgery to remove the cancer. Wound healing problems after surgery are frequent and can result in serious complications. The chance of having a wound problem after soft tissue sarcoma surgery is estimated at 43% in the lower extremity when the area is treated with radiation before the surgery. A wound healing problem after surgery requires extensive additional medical care and often one or more repeat surgeries to get the wound to heal. It is painful and associated with decreased quality of life. We hypothesize that using a device to assess blood flow during the operation may help determine which patients are likely to have problems. This device could indicate the need for additional treatments during the first surgery which could help avoid problems. The aim of this study is to compare the blood flow of the skin during the surgery and whether any problems occur with healing after surgery. This information could lead to a change in the way doctors decide whether additional treatments are required to improve patient outcomes.

IN OTHER WORDS

Surgery to remove sarcoma in the arms or legs has a high risk of wound healing problems. These can result in need for more surgeries and negatively impact quality of life. Assessing blood flow during the surgery may help predict and prevent wound problems.

Charles Martin III, MD

Cleveland Clinic Lerner Research Institute

SOLID LIVER KIDNEY & SOFT TISSUE TUMOR

William C. Mulligan VeloSano Pilot Award in memory of Stuart M. Schreiber

3D Holographic Fusion of Multimodality Guidance and Navigation (3D HoloFusion) for Percutaneous Multiprobe Ablation of Tumors

This VeloSano 7 pilot project will advance our three-dimensional (3D) augmented reality system, developed at Cleveland Clinic, to significantly improve the use of medical imaging during percutaneous thermal ablation of solid cancerous tumors. Instead of using 2D image guidance for visualization and planning during this increasingly utilized minimally invasive treatment, this system uses a head mounted display (Microsoft HoloLens 2) to project 3D guidance, based on multimodality imaging, directly to the targeted region of the operative site. This stereoscopic image guidance fuses holograms of real-time ultrasound imaging, volume CT or MRI image data, and multiple simultaneously tracked thermal ablation devices, each with a modeled thermal ablation zone, for accurate navigation directly to the targeted tissue, which is particularly important for tumors undergoing motion and in challenging anatomic locations. This will enable the planned multiprobe thermal treatment volume to better conform to the size and 3D shape of each tumor in comparison with the use of 2D monitors in present standard-of-care image guidance. Improved conformance of the 3D treatment zone will also decrease the risk to nearby healthy tissue and critical structures. This project will demonstrate feasibility from bench verification to clinical evaluation with amendment to an approved IRB protocol, including quantification of sufficient tumor coverage with an acceptable minimum overtreatment. By supporting clinical decision-making and 3D treatment planning, this 3D augmented reality system can increase the effectiveness, safety, and efficiency of the treatment, leading to fewer procedure-related complications, less tumor recurrence, and improvement in cancer patient care.

IN OTHER WORDS

This project will advance the development of a three-dimensional (3D) augmented reality system during treatment of solid cancerous tumors through the skin. Instead of using a 2D screen and a computer mouse during surgery, this system projects 3D holographic guidance, based on medical imaging, directly to the targeted area of the body, in combination with positional tracking of multiple surgical devices. By supporting clinical decision-making, this 3D augmented reality system can make it easier for the surgeon to perform the treatment, leading to fewer procedure-related complications, less need for repeat treatment, and improvement in cancer patient care.

Hrishikesh Mehta

Cleveland Clinic Lerner Research Institute

BLOOD CANCER

Pediatric Pilot Award

Chemoprevention of Pediatric Leukemia Predisposition Syndromes Through Nonsense Suppression

Inherited bone marrow failure syndromes (IBMFS) constitute leukemia predisposition syndromes with a high rate of transformation to acute myeloid leukemia (AML). In children, AML has a 5 year survival rate of ~65%, but the prognosis of AML associated with IBMFS is poorer. Severe congenital neutropenia (SCN) and Shwachman Diamond Syndrome (SDS) are IBMFS with loss of neutrophil production. Over the years better disease management has led to increased survival, however development of AML is now the primary risk factor for death. The poor prognosis of AML makes it imperative to find novel treatment options that can prevent AML in vulnerable populations. I propose a novel approach to target both diseases prior to development of AML by taking advantage of a common factor in both diseases. I propose that suppressing the effect of nonsense mutations can be used to prevent AML. In SCN the nonsense mutations are acquired in the gene encoding the granulocyte colony stimulating factor receptor (CSF3R), while in SDS nonsense mutations make up majority of the germline mutations found in the Shwachman-Bodian-Diamond syndrome gene (SBDS). The result of these nonsense mutations are formation of truncated proteins that result in a pre-leukemic state. I propose that the nonsense mutations can be targeted using a nonsense suppression drug called Ataluren, which allows expression of the full-length neomorphic protein, instead of the truncated protein. Approved in Europe for the amelioration of Duchenne muscular dystrophy, Ataluren has not been evaluated in other conditions.

IN OTHER WORDS

Nonsense mutations result in truncated proteins that promote a pre-leukemic state in some children. Using a small molecule approach to manipulate the cellular protein making machinery to skip the nonsense mutations will promote normal full length protein. This approach will not only prevent development of cancer and treat the underlying disease.

Richard Padgett, PhD

Cleveland Clinic Lerner Research Institute

LEUKEMIA/BLOOD CANCER

Matthew and Stacey Litzler VeloSano Pilot Award

Myeloid neoplasms as a Global Spliceopathy: Implications for Molecular and Immune Pathogenesis

A number of diseases of the bone marrow, known collectively as myeloid neoplasms, cause losses of one or more type of blood cells and often progress to leukemia. These are mainly caused by the growth of clones of mutant cells in the bone marrow. Most of these diseases are difficult to treat and current therapies do not produce lasting remission so the identification of new targets is needed. Of the common mutations seen in these clones, over 60% affect genes that encode proteins involved in processing mRNAs in the nucleus by splicing. We have analyzed large collections of bone marrow samples from patients and healthy individuals to identify the molecular effects of these mutations. We identified hundreds of potentially useful targets in our computer analysis. Now we need to identify he useful ones by biochemical and further computational methods. First, we want to make sure the mis-processed RNAs are made in cells we can study and are not found in any normal tissues in the body. Then we need to show that they can actually make novel proteins. Then we need to show that these proteins can be correctly presented to the immune system. In the end, we will have lists of validated novel proteins that can serve as diagnostic markers and, we hope, as new targets for immunotherapies to suppress or eliminate these diseased clones in the bone marrow.

IN OTHER WORDS

We have found many potential new proteins made only in leukemic bone marrow cells. We need to find which ones might be useful for diagnosis and/or treatment. We plan to produce ranked lists of candidates that have the best chances of being useful.

Ruth Keri, PhD

Cleveland Clinic Lerner Research Institute

BREAST CANCER

Sandy’s Domestiques VeloSano Pilot Award

SMC2 Regulation of Chromosomal Instability in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is a highly aggressive disease that disproportionately affects young and African American women. Women diagnosed with TNBC are treated with chemotherapy and they frequently develop metastatic disease within 2-3 years. Once this occurs, there are very limited treatment options and the prognosis for these patients is poor. A recent expert analysis of breast cancer needs indicated that identifying new therapies for TNBC was a top 10 priority. In this regard, we have recently identified a protein, called SMC2 that we anticipate controls the processes by which TNBC cells become deadly. We found that tumors that have more SMC2 tend to be more malignant. We also found that TNBC cells need SMC2 to continue to grow. In this proposal we will discover how SMC2 controls TNBC growth. We hypothesize that SMC2 governs the way DNA is maintained in tumor cells as they are growing. We also propose that SMC2 controls the activity of genes that drive metastatic and drug-resistant features of TNBC cells, particularly resistance to chemotherapies. This VeloSano project will address both of these questions using state-of-the-art microscopy and genomic analyses of the cells. Lastly, we will ensure the clinical relevance of the project by testing our findings in tumor samples from patients with TNBC. If we find that SMC2 orchestrates TNBC biology, developing therapies that inhibit its function should be straightforward because it has a chemical property commonly targeted with new drugs. Such drugs may ultimately improve patient outcomes from this disease.

IN OTHER WORDS

This project aims to develop a better understanding of what drives triple negative breast cancer (TNBC) so that we can design effective therapies for this disease. We will investigate whether SMC2 causes TNBC to acquire changes in their DNA that make them more malignant and difficult to treat. This may reveal that SMC2 is a good target for developing a new therapy for TNBC.

Sarah Vij, MD

Cleveland Clinic Glickman Urological & Kidney Institute

MANY CANCER VARIETIES

Harry H. Esbenshade VeloSano Pilot Award

Fertility Potential Preservation in Boys Facing Infertility-Causing Diseases or Treatment Regimens with Testicular Tissue Freezing

Currently, no fertility preservation options are available for pre-pubertal boys who are not yet producing sperm. However, experimental techniques are currently being developed to provide future alternatives for patients that preserve their testicular tissue/cells. In order to take advantage of these and future technologies, patients must harvest and preserve their testicular tissue prior to disease or treatment associated with infertility. This study will harvest testicular tissue from eligible patients prior to undergoing therapy that will impact future fertility. Separate portions of the tissue will be banked for future research use and cryopreserved and maintained for participating patients as a resource for future elective procedures to attempt fertility restoration.

IN OTHER WORDS

Pre-pubescent boys undergoing cancer treatments do not presently have any fertility preservation techniques or therapies available. This study aims to harvest testicular tissue prior to gonadotoxic therapies for future utilization and research regarding future options for fatherhood. Additionally, this study will determine if undergoing testicular tissue cryopreservation reduces distress during and after cancer treatment.

Li Wang

Cleveland Clinic Taussig Cancer Institute

BREAST CANCER

Pilot Award

Examine the Role of VISTA in Regulating Anti-Tumor Immunity in Breast Cancer

Triple-negative breast cancer (TNBC) is a challenging disease with high rate of relapse and mortality following chemotherapy. While FDA has approved PD-L1/PD-1 inhibitors for TNBC treatment, the overall low response rate warrants effort to target new non-redundant immune checkpoint receptors (ICR). The V domain Immunoglobulin Suppressor of T cell activation (VISTA), first discovered by this study PI, Lily Wang, is a novel ICR that critically controls anti-tumor immunity and is a promising target for treating diseases resistant to PD-1 inhibitors. However, the immuno-regulatory mechanisms of VISTA in multiple immune cell lineages remain incompletely understood, which hampers the proper development of VISTA-targeting reagents as well as the identification of early biomarkers that could predict response.
This proposal focuses on defining the novel mechanisms by which VISTA regulates immunosuppressive myeloid cells. Our overall hypothesis is that VISTA promotes the differentiation and functions of tumor-associated MDSCs, which in turn impairs anti-tumor adaptive immunity and results in therapeutic resistance in TNBCs. We will test our hypothesis by first generating and characterizing novel GEMM breast cancer models where VISTA is specifically deleted in myeloid cells (Aim 1). We will further investigate the expression of VISTA in human TNBCs and determine how VISTA expression pattern is associated with the tumor transcriptomic profiles and clinical outcomes (Aim 2). We expect that these studies will establish VISTA as a causal factor for resistance and recurrence in TNBCs and lay the foundation for developing and testing VISTA inhibitors for improving breast cancer immunotherapy.

IN OTHER WORDS

Triple negative breast cancer (TNBC) is associated with high rate of relapse and mortality and shows overall low response rate to immunotherapies. These unmet clinical needs warrant efforts to identify new therapeutic targets. This project aims to define the mechanisms and prognostic roles of a novel immune checkpoint protein VISTA in mediating immunosuppression in breast cancer. Our results will lay the foundation for developing and testing VISTA inhibitors for improving breast cancer immunotherapy.

Jennifer Yu, MD, PhD

Cleveland Clinic Taussig Cancer Institute

BRAIN CANCER

Béla Szigethy VeloSano Pilot Award in memory of Maria Szigethy

Hypoxia-Regulated IncRNA in Glioblastoma Progression

Glioblastoma is an incurable primary brain tumor that is characterized by regions of hypoxia and marked resistance to radiation. Glioma cancer stem cells are a highly malignant subpopulation of cells that are highly resistant to standard treatments. These cancer stem cells are frequently located in hypoxic areas, making them more even difficult to kill with radiation. Cancer stem cells therefore play an important role in disease recurrence. Long non-coding RNAs (lncRNAs) have recently been found to be dysregulated in cancer. LncRNAs have multiple functions including regulation of gene expression. We have found that the lncRNA Lucat1 is an important regulator of glioma cancer stem cell response to hypoxia. Lucat1 is frequently overexpressed in glioblastoma and is associated with poor prognosis. Our data support that Lucat1 is induced by hypoxia and reinforces hypoxia signaling. In this study, we propose to study how Lucat1 regulates glioma cancer stem cell response to hypoxia and test inhibitors of Lucat1. If successful, our findings will provide a new therapeutic approach for targeting glioma cancer stem cells in hypoxia to improve glioblastoma treatment. This treatment strategy may be extended to other cancers including smoking-associated lung cancer and renal cell cancer that express high levels of Lucat1.

IN OTHER WORDS

Glioblastoma is an incurable brain tumor. Our studies will identify a vulnerability of the most aggressive cancer cells and offer a novel targeting strategy. These studies are expected to provide new treatments for patients with glioblastoma.

Jianjun Zhao, PhD

Cleveland Clinic Lerner Research Institute

MULTIPLE MYELOMA

Marc Harrison Impact Award

pERP1 as a Novel Therapeutic Target for Multiple Myeloma

Multiple myeloma (MM) is an incurable and heterogeneous plasma cell malignancy. Even though with current drug development including antibody drug such as daratumumab targeting CD38 in clinic, MM patients will finally develop drug resistance. Novel targeted therapy is urgently needed to overcome the multiple drug resistance. The aim of this proposal is to define the potential of pERP1 as a novel therapeutic target for MM. pERP1 is a helper for immunoglobulin assembling and secretion and specifically highly expressed in MM cells. We also found pERP1 was highly expressed on the surface of MM cell lines and the plasma cells from MM patients compared with plasma cells from donor. We hypotheses that blocking the function of pERP1 positive plasma cells in bone marrow using neutralization antibody may have therapeutic benefit MM patients. Since the need for novel and targeted therapy to overcome the drug resistance of end stage MM patients, this study is timely and translational, and potentially leads to better understanding of future treatment of this hematological malignancy.

IN OTHER WORDS

Increasing our understanding of the pathogenesis of hematopoietic malignancies will ultimately facilitate the translational research towards the discovery and development of novel therapy for patients. Our project aims to determine the potential use of pERP1, an immunoglobulin chaperone highly expressed in plasma cells, as a novel MM therapeutic target. If validated, this will be an important advancement in the treatment of MM. Furthermore, optimization of a monoclonal antibody to accurately neutralized the surface expression of pERP1 in patients will be extremely helpful in a clinical setting if pERP1 is validated as a therapeutic target for MM.

Miriam Cremer, MD

Cleveland Clinic Women’s Health Institute

CERVICAL CANCER

Pilot Award

Feasibility of Moving to Primary HPV Testing vs Co-Testing for Cervical Cancer Screening at Cleveland Clinic

Co-testing with cytology and HPV assays is the most common modality of cervical cancer screening in the United States, but current guidelines recommend transitioning to primary HPV screening. This study will address barriers to this transition, principally determining if false negative HPV tests in patients with high-grade precancers are due to the presence of non-oncogenic HPV types, rather than faulty screening. We will also evaluate readiness for this transition among key stakeholders in the Cleveland Clinic, a large and influential health system that has the potential to pioneer this important transition in cervical cancer prevention.

IN OTHER WORDS

The most common cervical cancer screening method in the US is co-testing (combining Pap and HPV testing), but guidelines now recommend transitioning to primary HPV screening. This study will address barriers to this transition, particularly if false negative HPV tests in patients are due to the presence of non-oncogenic HPV types. We will also evaluate perceptions of this transition among stakeholders in the Cleveland Clinic.

Sudipto Mukherjee, MD, MPH

Cleveland Clinic Taussig Cancer Institute

RARE CANCERS AND BLOOD DISEASES

Impact Award

Development of Rare Cancers and Blood Diseases Program

In the US, rare cancers now comprise approximately 25% of all cancers according to Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The outcomes of rare cancers are typically poor with 50-60% 5-year survival relative to the general population. Hematopoietic system of all organ systems have the largest share of cancers or diseases listed as rare – 38% of all hematologic malignancies. Rare hematologic cancers or disease in general get less scientific consideration and financial support than their more frequent counterparts. Clinical challenges in treating rare hematologic cancers or diseases frequently stem from their low prevalence, often incorrect and late diagnosis, clinical unfamiliarity with these diseases, lack of approved therapies, paucity of clinical trials and shortage of accessible cancer registries and tissue banks. Cleveland Clinic’s Taussig Cancer Center formally established the Rare Cancers and Blood Diseases Program in 2020 with three goals in mind – to offer specific clinical, surgical or pathology expertise for accurate and timely diagnosis of these conditions, enhance access to care for these patients and offer therapies (approved or experimental) based on translational research. The objective of this Impact award is to accelerate research in understanding the molecular mechanism of these diseases, develop therapeutic platforms for rapid testing of novel agents or repurposed drugs and establish disease registries for understanding the natural history of these diseases.

N OTHER WORDS

In this study, we propose to conduct agnostic genomic evaluation using whole exome sequencing (WES) of a variety of rare hematologic diseases grouped under histiocytic disorders, and Castleman’s disease (CD) and its variants to further elucidate our understanding of the molecular bases of these disorders and identify potential actionable mutations that can be targeted with therapies in the context of clinical trials.

Susan McInnes, MD

Cleveland Clinic Taussig Cancer Institute

PALLIATIVE MEDICINE AND SUPPORTIVE ONCOLOGY

Impact Award

A Pilot Study of Scrambler Therapy for Refractory Neuropathic Pain in Cancer Patients

Neuropathic pain (NPP) is a common, debilitating, painful condition affecting up to 50% of cancer patients, whether from chemotherapy, surgery or complications of cancer. A patient may be cured of their cancer and yet be left with ongoing chronic severe painful burning, stinging or shooting pain. NPP profoundly affects quality of life (QOL), functional status, sleep, balance and mood, but there are few therapeutic options for successful control. Options for NPP treatment include gabapentinoids, anti-depressants and opioids, none of which are consistently effective or well-tolerated. Many patients are seeking non-pharmacologic approaches to pain management. Scrambler therapy is a novel noninvasive cutaneous neuro-stimulatory treatment, administered by physicians or other independent practitioners, that has shown up to 50-90% response for NPP when tested at other leading NCI-designated comprehensive cancer centers such as Mayo Clinic, MD Anderson and Johns Hopkins. The therapy is tailored to individual patient symptoms and one cycle is daily 30-minute treatments up to ten times over a 2-week period. There have been no safety concerns or serious side effects. This award would offer an opportunity to impact QOL for cancer patients suffering from a variety of different cancers.

IN OTHER WORDS

This study intends to advance cancer survivorship and quality of life for patients with NPP followed by palliative medicine by treating their pain using scrambler therapy. Exploring efficacy and practical integration of non-pharmacologic, especially non-opioid therapies, aligns with institutional, state and national efforts to reduce the potential adverse impact of long-term opioid therapy, both for individual patients and the community.

Cleveland Clinic is part of the Case Comprehensive Cancer Center (CCCC), which is designed to promote research collaboration across the three member institutions: Cleveland Clinic, Case Western Reserve University and University Hospitals.  Team science is increasingly important for successful cancer research, and the CCCC is an excellent example of such teamwork across these three organizations.  CCCC has had a team participate in VeloSano since the second year, and as part of our collaboration they received $500,000 of the dollars raised in 2020 to support cancer research projects.