Seven Cancer Research Projects Funded in Fall 2021 RAP Cycle

Can you describe the focus of your project in a few sentences? 

Thank you! In this project we are aiming to identify a signature of super-enhancer dysregulated genes that associate with cancer patients’ poor survival outcomes across most or all cancer types. To approach this, we will use a combination of public webtools and our basic bioinformatics knowledge to analyze publicly available cancer datasets containing epigenetic, genomic, cellular, and clinical information collected from patients. We recently organized our approach into a pipeline and by following it, we successfully identified and experimentally validated NSMCE2 and MAL2 as two genes that are dysregulated by super-enhancers in breast tumors, and for which high transcript levels are associated with breast cancer patients’ negative survival and poor response to chemotherapy. Super-enhancers are potent genomic enhancers shown to be involved in the transcriptional over activation of oncogenes in certain cancers. The disruption of super-enhancers by pharmacological interventions is widely studied and currently being tested in clinical trials. Thus, understanding super-enhancer dysregulation and their target genes is critical and has great potential for generating more specific therapeutic interventions to improve the treatment of cancer.

What motivated you to pursue this particular project? What do you find most exciting about this research?

Multiple reasons motivated my group and myself to pursue this project. First, cancer recurrence, especially for patients diagnosed with breast cancer, continues to be a major problem for certain groups of patients treated with standard therapies. Second, thanks to current advancements in sequencing and computational technology, we now have access to a wide amount of genomic, genetic, cellular information collected from cancer patients that are diagnosed with the disease, treated, and followed up for years. This information can be extremely useful for identifying pathways and mechanisms that promote the disease and for finding patterns of gene expression that may provide certain patients with resistance to cancer therapies. Third, I know from experience that transcriptional dysregulation by super-enhancers is an important mechanism that provides cells with cancer characteristics. A few years ago, I demonstrated that super-enhancers are involved in the overactivation of the immune suppressive signal CD47 in breast tumors that are classified as hormone positive. Thus, my lab’s mission now is to understand what other genes are dysregulated by super-enhancers not only in one breast cancer subtype.

The most exciting part of this project is to think about the potential that our proposed pipeline has for the discovery of a cohort of genes and mechanisms of gene regulation that may be common in different cancer types or across patient populations and that could be responsible for creating resistance to standard cancer therapies. Best of all, is that we can find these candidate genes and make predictions by mining existing public cancer databases. We believe our pipeline will have a powerful value in the cancer field since we recently validated it by analyzing breast cancer datasets and by pharmacologically perturbing and silencing the identified candidate super-enhancer dysregulated genes. Our approach offers an initial platform for the discovery of novel dysregulated genes not often mutated and potential therapeutic targets that may benefit a group of patients for which no treatment is currently available.

Can you describe the focus of your project in a few sentences?

Oncogenic FOXO1 fusions drive dismal outcomes in adolescents and young adults with rhabdomyosarcoma. From a genetic screen, we discovered that cells harboring this fusion have enhanced dependency on the ubiquitin hydroxylase UCHL5. Our preliminary data lead us to hypothesize that UCHL5, as part of the INO80 chromatin remodeling complex, functions to resolve transcriptional stress that arises at PAX3-FOXO1 bound superenhancers. This proposal aims to test this proposed mechanism, and use preclinical models to determine whether UCHL5 is a selective therapeutic target in fusion positive rhabdomyosarcoma

What motivated you to pursue this particular project? What do you find most exciting about this research?

The foundation of this project was to harness functional genomics to generate new, therapeutically relevant hypotheses that take aim at a fusion transcription factor at the heart of 30 years of disappointing clinical trials. Our molecular understanding of how PAX3-FOXO1 rewires cells has been slow to come, and thus far has not translated into improved therapies; in the meanwhile, we continue to see patients relapse after increasingly intensive, but ultimately biologically un-targeted, treatments. I am excited at the prospect of using genetic interaction mapping to ultimately improve outcomes for the patients I see with this devastating disease.

Can you describe the focus of your project in a few sentences?

Lung cancer screening can save lives, but it is a newer test, and there are many unanswered questions about its use. As the largest integrated health system in the US, the VA has an incredible breadth of information - but so far, we have limited ability to tease apart who has received screening for lung cancer and who hasn't. To isolate the impact of screening asymptomatic individuals, we need to exclude these diagnostic tests which are just part of regular clinical care (that is, prompted by signs or symptoms of cancer). I am developing a new tool to do this quickly and accurately. I will then follow Veterans who receive lung cancer screening to see its impact on their health. 

What motivated you to pursue this particular project? What do you find most exciting about this research?

I work as a primary care doctor at the VA. One of the challenges in primary care is to accurately convey the risks and benefits of cancer screening in a brief clinic visit - and I say this as someone who has a PhD in cancer screening epidemiology! This challenge is what motivated me. My goal is to help personalize screening decisions, so that PCPs can more easily talk with patients about the real-world risks and benefits of lung cancer screening. That way, we can help individuals make informed decisions, and maximize the benefit of lung cancer screening. 

Can you describe the focus of your project in a few sentences?

Glioblastoma is a highly malignant and invasive brain tumor with a poor prognosis that arises from the ineffective immune response that the tumor elicits. My proposal, “Replicating Retroviral Delivery of Immunomodulatory Genes to Glioblastoma,” focuses on treating glioblastoma with a replicating retrovirus that will spread through the tumor while carrying a gene for RLI, an interleukin-15 fusion protein that stimulates an anti-tumoral T-cell response. We have encouraging pilot data suggesting that this virus is effective against a mouse model of glioblastoma that mimics the human tumor’s lack of immunogenicity and aggressive biology. In our RAP proposal, my lab will explore combining this virus with systemic immunotherapy and other cytokines or cytotoxic gene therapies to enhance the efficacy of this virus.

What motivated you to pursue this particular project? What do you find most exciting about this research?

My clinical practice as a neurosurgeon operating on glioblastoma patients and seeing first hand how compromised their anti-tumor immune response is motivated me to pursue this particular project. I did a PhD over 20 years ago developing viruses for brain tumors and this has been a passion of mine since then. I am excited about getting this innovative virus from the lab to the clinic in order to help patients with this devastating cancer. 

Can you describe the focus of your project in a few sentences?

Endocrine surgeons have recently started using devices that can detect autofluorescence in parathyroid tissue illuminated by near-infrared (NIR) wavelength light. These devices are mainly for helping visualize the parathyroid glands in situ to avoid inadvertent injury during anterior neck surgical procedures. Because parathyroid glands and adrenal glands share certain secretory properties as endocrine organs, we wondered whether adrenal glands would also prove to be NIR auto-fluorescent. It turns out that adrenal glands are highly auto-fluorescent under NIR, and the auto-fluorescent signal appears to arise from a specific cellular layer in the adrenal cortex. This got us thinking that NIR autofluorescence might have clinical utility in distinguishing benign adrenocortical adenomas from malignant, highly lethal adrenocortical carcinomas (ACCs). Differentiating between these tumor types can be challenging and currently requires pathologists to apply a cumbersome, time consuming, and potentially subjective set of morphological criteria to render a diagnosis. Based on our preliminary results suggesting measurable differences in NIR signal among adrenal tumors, we will retrospectively test a series of adrenal specimens to see if NIR autofluorescence can help distinguish benign from malignant adrenal tumors and perhaps be useful as a tool for visualizing tumor/normal tissue margins and for detection of ACC cell lymph node metastases that would otherwise have been missed.

What motivated you to pursue this particular project? What do you find most exciting about this research?

ACCs are very aggressive cancers and anything that can help improve accurate, timely identification and classification of adrenal tumors would be of significant benefit to the patient. Because the NIR method exploits the intrinsic auto-fluorescent properties of adrenal tissue, no injectable dyes, complex stains, or processing are required to visualize the signal. The speed, low cost, and simplicity of the assay makes it especially appealing even as a potential intraoperative tool, where real-time inspection of cryosections in the operative suite could provide immediate diagnostic information. We are super excited to explore the potential clinical utility of a new, easily implemented tool that could streamline and improve a very challenging diagnostic classification problem in endocrine surgery. In addition, the research allows clinicians and translational scientists to combine forces and minds to put forth tangible, exciting science for the benefits of our patients.

Can you describe the focus of your project in a few sentences? 

This is a RAP Team Science award, with myself and Drs. Jennifer Grandis and Charly Craik serving as PIs. Dr. Grandis and I have co-invented a novel drug that inhibits the oncogenic action of STAT3, a transcription factor that contributes to a broad variety of cancers. The drug is a first-in-class oligonucleotide compound that we refer to as STAT3 decoy. To move the STAT3 decoy into clinical testing the FDA has asked us to develop a pharmacokinetic assay to be able to detect this short oligonucleotide in the blood of cancer patients. Conventional methods for detection of drugs have proved difficult for this drug. We have teamed with Dr. Charly Craik, who has expertise in identifying Fab antibody fragments against unique targets, to identify Fabs against our oligonucleotide drug. The Fabs will then be used to generate a sandwich ELISA assay for detection of the STAT3 decoy in biological specimens.  

What motivated you to pursue this particular project? What do you find most exciting about this research?

STAT3 is hyperactivated and/or overexpressed in a majority of human solid tumors, contributing to unregulated tumor growth and resistance to conventional anti-cancer drugs. STAT3, like other transcription factors, is notoriously difficult to target with small molecule inhibitors, and there are no effective inhibitors of STAT3 in clinical use. Our STAT3 decoy has an entirely unique mechanism of action and has proven highly effective at inhibiting STAT3 and tumor growth in preclinical studies. We believe a large number of cancer patients could benefit from this drug. However, we have been unsuccessful at developing a pharmacokinetic assay for the drug using conventional methods of drug detection. We are excited to team with Dr. Craik to pursue the novel approach of identifying Fabs that detect our oligonucleotide drug with high affinity and specificity. Using the cutting-edge techniques developed in Dr. Craik’s lab we anticipate identifying Fabs that can be used to generate a sandwich-based ELISA, satisfying a requirement of the FDA and allowing us to move the STAT3 decoy into clinical evaluation.

This is a RAP Team Science award led by investigators Mary Barcellos-Hoff, PhD, and Noriyuki Kasahara, MD, PhD.