PROJECT 1: Unraveling and exploiting the molecular mechanisms unique to Alternative Lengthening of Telomeres (ALT), thereby allowing therapeutic targeting of a substantial proportion of cancers. Unlimited replication is a key hallmark of cancer allowing cancer cells to evade both replicative senescence and catastrophic telomere dysfunction-induced chromosomal instability. While the majority of cancers overcome these critical barriers via upregulation of telomerase, a telomere-specific reverse transcriptase, a subset of cancers maintains telomere lengths by a telomerase-independent mechanism, termed Alternative Lengthening of Telomeres (ALT). ALT is strongly associated with recurrent, cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin-remodeling complex. Unraveling and exploiting the molecular mechanisms unique to ALT holds tremendous potential for therapeutic targeting in a significant proportion of cancers. By comprehensively understanding the intricate molecular pathways involved in ALT, we aim to identify key components and vulnerabilities specific to this mechanism. Armed with this knowledge, therapeutic strategies can be developed to disrupt ALT-associated processes and selectively target cancer cells relying on this alternative telomere maintenance pathway. Such targeted interventions have the potential to offer more effective and tailored treatments, offering hope for patients with ALT-positive cancers.

DOD Rare Cancers Research Program Idea Development Award (PI: Heaphy; Co-Investigator: Flynn)

PROJECT 2. Mapping the tumor microenvironment using spatial transcriptomic profiling technologies. Spatial transcriptomic profiling is an innovative technique that provides a comprehensive understanding of the tumor and its surrounding microenvironment at a cellular level. Through integration with traditional histology, this approach allows for the simultaneous visualization and molecular characterization of individual cells within their spatial context. In the context of tumors, spatial transcriptomic profiling enables the identification and mapping of specific gene expression patterns within the tumor cells, as well as in neighboring stromal, immune, and vascular cells. This multidimensional information sheds light on the intricate interplay between the tumor and its microenvironment, uncovering critical insights into tumor heterogeneity, immune cell infiltration, and other key biological processes. By capturing the spatially resolved gene expression landscape, spatial transcriptomic profiling holds immense promise for advancing our understanding of tumor biology and guiding the development of targeted therapeutic strategies.

Neuroendocrine Tumor Research Foundation Pilot (PI: Heaphy; Co-Investigator: Dries)

DOD Rare Cancers Research Program Concept Award (PI: Heaphy; Co-Investigator: Dries, Kulke, Assi)

American Cancer Society Pilot (PI: Dries; Co-Investigators: Ko & Heaphy)

NCI R21 (MPI: Heaphy & Dries; Co-Investigators: Kulke & Singhi)

PROJECT 3: Evaluating the translational potential of ALT as a prognostic biomarker. We previously characterized ALT across >6,000 primary cancers from over 90 different cancer subtypes. Through that comprehensive survey and others, significant fractions of ALT-positive cancers were found in some cancer types, including sarcomas, astrocytomas, pancreatic neuroendocrine tumors (PanNETs), hepatocellular carcinomas, and testicular germ cell tumors. While tumor type-dependent and context-dependent, ALT-positive cancers are generally associated with increased genomic instability and portend a poor clinical prognosis, particularly in cancer types that currently lack targeted therapies. Thus, we continue to evaluate the clinical utility of ALT, in combination with other biomarkers, as a prognostic biomarker for certain cancer types (e.g. PanNETs, gliomas, and sarcomas). The ultimate goal is to establish ALT as a robust prognostic biomarker that can guide clinical decision-making and enable personalized treatment strategies for patients with ALT-positive cancers.

PROJECT 4. Evaluate racial disparities and prostate cancer outcomes. Racial disparities in prostate cancer outcomes persist as a significant concern within healthcare systems worldwide. Numerous studies have shown that certain racial and ethnic groups, particularly African American men, experience higher incidence rates, more aggressive forms of the disease, and worse outcomes compared to other populations. Understanding the factors underlying these disparities is crucial for improving patient care and outcomes. Ongoing research has identified various discoverable radiological, genetic, and cellular components that may contribute to the observed differences. Radiological studies have revealed distinct imaging characteristics associated with aggressive prostate cancer in different racial groups, offering potential avenues for early detection and personalized treatment approaches. Genetic investigations have identified specific gene variants that may be more prevalent in certain racial populations, influencing disease susceptibility, tumor biology, and treatment response. Moreover, cellular studies have shed light on variations in the tumor microenvironment and immune responses, highlighting potential targets for therapeutic interventions. We plan to determine what new clinical and social determinants of health data are needed to develop and refine a comprehensive “risk signature” that will more accurately inform the best pathway to care for an individual patient, thereby leading to more equitable healthcare practices.

Clinical & Translational Science Institute – Boston University (PI: Heaphy; Co-Investigators: Campbell & Flynn)

Department of Medicine – Boston Medical Center (PI: Heaphy)

Boston Medical Center Cancer Research Innovator Award (PI: Heaphy; Co-Investigator: Mori)

PROJECT 5. Evaluating stromal senescence in prostate cancer as a novel target for prognosis and therapy. Cellular senescence is a complex and dynamic phenomenon characterized by a stable growth arrest and the acquisition of a distinct secretory phenotype. In the context of prostate cancer progression, stromal fibroblasts play a crucial role. These fibroblasts undergo senescence due to various factors, such as chronic inflammation, oxidative stress, or DNA damage. Once senescent, stromal fibroblasts secrete a range of factors, collectively known as the senescence-associated secretory phenotype (SASP), which can promote tumor growth and progression. SASP factors contribute to the activation of nearby cancer cells, promoting their survival, invasion, and angiogenesis. Furthermore, senescent stromal fibroblasts can remodel the extracellular matrix, creating a supportive tumor microenvironment. Therefore, cellular senescence in stromal fibroblasts plays a critical role in prostate cancer progression by fostering a tumor-promoting microenvironment and facilitating the malignant behavior of cancer cells. Using a patho-epidemiology approach, we are evaluating the overarching hypothesis that senescent stromal fibroblasts, especially if they elicit an inflammatory response, promote lethal prostate cancer.

NCI R01 (MPI: Platz & Meeker; site PI: Heaphy)

PROJECT 6: Evaluating the translational potential for the prognostication and risk stratification of tissue-based telomere length measurements. Given that dysfunctional telomeres contribute to genomic instability and promotes tumorigenesis, we and others, have hypothesized that increased telomere shortening in cancer cells would drive the evolution of cell clones capable of invasion, extravasation, and metastasis. In these studies, we demonstrate the clinical feasibility and utility of the “telomere biomarker” – variable telomere length among prostate cancer cells (cell-to-cell) and shorter telomere length in prostate cancer-associated stromal (CAS) cells. These findings highlight the translational potential of the telomere biomarker for prognostication and risk stratification for individualized therapeutic and surveillance strategies in prostate cancer. In collaboration with our Pathology and Cancer Epidemiology colleagues, we are evaluating the clinical utility of the telomere biomarker in 5 key areas:

  • At time of surgery (prognostication)
  • At time of biopsy (risk stratification)
  • Prediction of therapeutic efficacy
  • Prevalence of the biomarker by race, BMI, and smoking status
  • In other cancer types (breast, ovarian, pancreas)

NCI R01 (MPI: Meeker & Heaphy)