The Convergence Institute focuses on identifying, adopting, and producing novel technologies to address key challenges in cancer research and supporting their accessibility to the Hopkins community.
We have adapted CyTOF, imaging mass cytometry, and CODEX for widespread correlative analysis of clinical trials, leading to its dissemination in the Flow/Mass Cytometry and Technology Development and the Tumor Microenvironment Lab.
Support for these and other clinically relevant projects and emerging technology development will be achieved through pilot grant projects, fostered interdisciplinary collaborations, and educational and training initiatives.
Institute members are active in many multi-center consortium projects, such as Break Through Cancer, National Cancer Institute Cancer Systems Biology, Informatics Technologies for Cancer Research, and Translational and Basic Science Research in Early Lesions (TBEL).
Mapping the complex interactions of tumor cells with normal cells that grow around them
Through collaborations with genomics and proteomic technology companies, we are advancing state-of-the-art single-cell technologies and spatial molecular technologies to uncover the function of cells in the tumor at new scales. The Convergence Institute uses these technologies as standard practice in our clinical trials. This research enables us to uncover biomarkers to predict the effect of new therapeutic strategies and discover new drug development targets. Dr. Luciane Kagohara was selected participate in 10X Genomics’ Clinical Translation Research Network for translational applications of spatial transcriptomics; and Dr. Robert Anders leads a nationwide working group to adapt the CODEX (CO Detection by Indexing) spatial proteomics technology for translational research. We are also broadly disseminating these technologies to the greater Johns Hopkins University community through founding a new cancer center shared resource led by Dr. Won Jin Ho. This shared resource provides single-cell and spatial proteomics using Mass Cytometry (CyTOF) and Imaging Mass Cytometry (IMC) at scale to investigators conducting laboratory and clinical research.
Patient avatars for therapeutic selection
Patient-derived organoids are 3-dimensional cell cultures created from each patient’s cancer cells that can be used to examine specific characteristics of a patient’s tumor. Dr. Jackie Zimmerman and Dr. Richard Burkhart have developed methods to co-culture tumor cells and their surrounding normal cells, such as fibroblasts and immune cells, to create a model for testing new drugs to individualize treatment that will most benefit each patient. In collaboration with the Department of Pathology, this discovery work is now being adapted to test patient tumors for drug sensitivity in clinical trials.
Pilots Fostering Innovation
The Convergence Institute provides an incubator for transdisciplinary research blending new technologies for biomedical research with potential clinical applications. To achieve this research goal, our pilot grants program, led by Dr. Daniel Laheru and Dr. Andrew Ewald, offers researchers across the University the opportunity to form new teams to invent new technologies for cancer research and expedite their adoption for clinical practice. These pilots provide a high-risk, high-reward testing ground that provides the foundation to develop future large-scale team science projects that can leverage additional funding mechanisms for the Institute. Out of 12 applications to the program, two projects led by Dr. Nathaniel Brennen and Dr. Nilofer Azad were selected for awards at $50,000 each due to their innovation and impact on predictive medicine.
Multi-Data Approach to Determine Drug Viability in Prostate Cancer
Dr. Nathaniel Brennen’s collaborative project integrates cutting edge spatial transcriptomic and proteomic technology and with clinical research to ask the question, “Does LSD1 inhibition via Bomedemstat promote anti-tumor immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients?” Bomedemstat is an oral medication used to treat many types of cancer by promoting an immune response to deactivate LSD1, a protein known to drive the growth of tumor cells in certain types of cancer. This project is leveraging patient samples from an ongoing clinical trial of Bomedemstat in mCRPC patients to understand:
1) Spatially resolved infiltration of immune cells and their cellular interactions
2) The spatial distribution of drug penetration within the tumor
The spatially resolved data from this project gives an in-depth analysis of drug distribution and effects within the tumor that is more informative than bulk data information from standard analysis methods. The novel methodology in this project includes Applied Imaging Mass Spectrometry (AIMS) to determine spatially resolved drug distribution, staining and spatial imaging of 85 biological markers and proteins in a single sample using Nanostring GeoMx Deep Spatial Profiler (DSP), spatial transcriptomics analysis of gene expression, and ultimately integration of all of this data to understand changes to cellular interactions in response to Bomedemstat treatment.
Comparison of samples from patients that are known responders and non-responders this drug therapy will provide researchers with data to identify patients who will benefit from this treatment. This project will also advance the analysis platforms and data integration processes available to study other cancer drugs and their effects within the tumor.
Immune-Profiling and Genetic Analysis of Colorectal Patient Biospecimens from a Combination Therapy Clinical Trial
Nilofer Azad, M.D. submitted an application examining if “Phosphatidylinositol 3-kinase (PI3K) inhibition with copanlisib in combination with nivolumab will enhance CD8+ T cell infiltration and activation in the tumor microenvironment (TME).” Copanlisib is a therapeutic inhibitor of the Phosphatidylinositol 3-kinase (PI3K) protein, which is part of a molecular pathway involved in tumor cell survival and proliferation. Nivolumab is an immune checkpoint inhibitor drug approved for use in patients with specific defects in DNA repair. A recent clinical trial by Dr. Azad’s team testing these two drugs together showed significant success in some patients, indicating a possible synergy between the two drugs.
Comparison of biopsy samples before and after treatment, between patient subgroups of responders and non-responders, and between patients with and without mutations in PI3K may contain valuable information on:
1) The impact of this drug combination on the immune modulation within the tumor and its microenvironment
2) Biomarkers that could potentially differentiate patients who may benefit the most from this treatment
Leveraging the spatial proteomics capabilities of the Convergence Institute, changes in immune cell infiltration and composition and complex cell signaling pathway analyses will be performed in collaboration with Dr. Robert Anders’s group. Whole exome sequencing and muti-omic multivariate analysis of acquired data will be done with the Experimental and Computational Genomics Core and with the expertise of Dr. Yegnasubramanian’s team. These combined results will help researchers understand how these two drugs work together and spur new preclinical studies of improved combination therapies with nivolumab, copanlisib and other chemotherapeutic drugs. Avenues to directly translate technology-derived information differentiating patients that may derive the most benefit from this treatment into targeted patient clinical trials are also available.