Sidharth Mahapatra, MD, Ph.d.
Associate Professor, Division of Critical Care | University of Nebraska Medical Center
As a pediatric intensivist with an interest in neurocritical care working in a state with a punctuated incidence of pediatric brain tumors, I aspire to carve my academic niche studying pediatric medulloblastomas (MB), the most common malignant brain tumor of childhood. Serving as an intersection for my training in molecular neurobiology, my strong interest in translational science, and my burgeoning expertise in pediatric critical care medicine, I hope to significantly impact the long term survivorship of patients with high-risk medulloblastomas, who suffer high relapse rates and mortality.
My secondary clinical interest lies in the study of acute lung injury and pediatric acute respiratory distress syndrome (PARDS). I am an active member of the Pediatric Acute Lung Injury & Sepsis Investigators (PALISI). We have participated in several landmark study including the Pediatric Acute Respiratory Distress Incidence and Epidemiology (PARDIE) and are now engaged in the Prone and Oscillator in Pediatrics Clinical Trial (PROSpect) aimed at studying treatment strategies in severe PARDS. Over my career, I aspire to actively engage with collaborators in an effort to mitigate PARDS in the field of critical care.
Education Grants
2026-2027
2-Year Travel and Conference Budget
$11,500
This grant will fund travel for three Principal Investigators for SNO Conference (Society for Neuro-Oncology in Philadelphia) and One Principal Investigator to ISPNO (International Symposium on Paeditric Neuro-Oncology in Australia).
2021-2023
Collaboration with David Doss
$150,000
This unique award by Team Jack is significant since David Doss will be the first candidate UNMC and Creighton have worked together to train. These funds provide supplies for his work, while Creighton University provides salary support through the MD, PhD program.
His primary project is to repurpose FDA-approved drugs for the treatment of medulloblastoma. David has chosen 4 top candidates, i.e., nortriptyline, sertraline, simvastatin, and fluoxetine, from a list of 100 possible drugs. Each of these drugs has a favorable discordance score (>-0.3), a measure of how well these drugs can reverse the MB gene signature upon in vitro administration to cancer cells. They all also cross the blood-brain barrier and have a favorable safety profile in a pediatric population. The best of the 4 candidates is nortriptyline (48h IC50 ~7uM). He has thoroughly characterized its anti-neoplastic effects via MTT, colony formation, medullosphere formation, wound healing, western blotting, and FACS. He is showing these effects in 2 cell lines. Bulk RNA Sequencing data on NT’s impact on HDMB03 cells have identified pathways associated with mitochondrial and lipid metabolism that are impacted by NT. He has further confirmed mitochondrial dysfunction using Seahorse assay. Moreover, he has shown that NT can synergize with cisplatin, a common G3MB chemotherapy drug. He is getting ready to test the impact of NT+cisplatin in an animal model. We expect to submit a first-author MS of his work by summer.
David is well into his third year as an MD, PhD. David passed his candidacy exam in August 2023. He also submitted an F30 to NCI for his primary project which was not discussed. He is re-submitting his F30 this month. He is preparing his progress in a first-author manuscript. He also published his 3rd middle-author paper in February 2024 (PMID: 38093348). He has presented his research as an oral presentation at the Midwest Scientific Biomedical Research Forum (MSBRF). He will be presenting his work in Chicago at the annual AAP/ASCI/APSA Joint Meeting (April 5-7) and at the Midwest Clinical and Translational Research Meeting (April 8-9), for which he won a Trainee Award.
January 2020
International Symposium of Pediatric Neuro-Oncology Registration
$800
Research Grants
2020-2023
Chemosensitization of non-SHH/WNT medulloblastoma is regulated by miR-1253 | Project Complete
$330,000
We are now focused on thoroughly elucidating how iron regulation bestows aggressiveness to group 3 tumors. Our first in vivo studies revealed that ABCB7KO reduced orthotopic group 3 tumors and prolonged longevity. We also showed that artesunate, an anti-malarial drug that inhibits both ABBC7 and GPX4, is cytotoxic to G3MB cells and can synergize with cisplatin to kill tumor cells. We also have preliminary data showing that ABCB7KO alters the metabolomic profile of HDMB03 cells. With this additional data, we have resubmitted our R01 grant (March cycle) initially scored at 39%. We have been granted a Buffett Cancer Center Grant to continue this work.
Our secondary project relates to an oncogenic target of miR-1253, which we discovered and published earlier (PMID: 32145124). B7-H3 (CD276) is an immune checkpoint molecule that plays a critical role in tumor evasion. It is deregulated in a number of cancers, including medulloblastoma. With the help of our collaborator in the Department of Pharmaceutical Sciences (Dr. Paul Trippier), we have isolated a strong small molecule inhibitor of B7-H3 (Ni1). Paul has generated several analogs of this inhibitor by modifying key residues to make the inhibitor more potent. We are testing each of these inhibitors to determine the best set to advance into in vitro studies. Dr. DJ Murray from the same Department is investigating the pharmacokinetic and pharmacodynamic properties of these inhibitors to help us advance our studies in vivo. His group has shown that Ni1 is stable, has a half-life of 7 hours, and reaches high levels in the brain after intraperitoneal injection. Ni1 also has a good safety profile in mice. Once we have a critical mass of data, we will apply for a patent through UNeMED. We have been granted an Edna Ittner Pediatric Research Grant from UNMC to continue this work. We have also published a review of B7-H3 in BBA Reviews in Cancer
(PMID: 36028149).
2022-2024
Development of a Regional Pediatric Brain Tumor Core Facility at the University of Nebraska Medical Center
$226,350
With the help of our neurosurgery partner, Dr. Grace Lai, and her research coordinator, we are nearing IRB approval for our brain tumor specific tumor bank. I have also hired a research technologist II to help with sample procurement, storage, and processing. The ultimate aim is to generate cell lines, 3D organoids, and animal models from these banked tissues. We had developed a Scientific Review Committee to handle all requests for tissue from the tumor bank. This will include our neurosurgeons (Drs. Klugh, Salehi, Lai), our neurooncologist (Dr. Raulji), and pathologist (Jie Chen). The tumor bank will be housed in the Department of Pathology at UNMC, under the guidance of Dr. Jie Chen, neuropathologist. We do have a shaking incubator for the generation of brain tumor organoids, which will be undertaken by my lab. We have recently established a collaboration with the Children’s Brain Tumor Network (CBTN) who have expertise in organoid generation. I have worked to update all records and subgrouping data on retrospectively collected MB samples at UNMC (51 samples, 2003 – 2021). I have access to these and have updated our published data (GSE 148389, PMID: 32145124). Moving forward, we will be ready to collect samples of all pediatric patients with brain tumors.
2023-2026
Deep investigation of gene silencing on 17p13.3. identifies targetable vulnerabilities informing novel therapeutic strategies for pediatric medulloblastomas.
$481,143
The long-term objective is to identify key drivers of group 3 MB aggressiveness that can be targeted by drugs that synergize with current chemotherapy to generate more efficacious therapeutic options for group 3 patients. Based upon these preliminary observations, they hypothesize that combined inhibition of ABCB7 and B7-H3 will attenuate group 3 medulloblastoma tumor aggressiveness and sensitize tumors to cisplatin cytotoxicity. The overall objective is to show that combining ABCB7/B7-H3 inhibition with classic chemotherapy is efficacious in killing group 3 tumors while delineating the mechanisms triggered by inhibiting each oncoprotein.