Description of Research Expertise

Improved Therapeutic Response via Metabolic Modulation
Development of a safe and reproducible method to selectively acidify and deenergize human cancers. Specifically, we seek to employ the natural tendency of cancers to convert glucose to lactate as a method for selective intracellular acidification, which is known to potentiate tumor response to chemotherapy, radiation therapy, hyperthermia, and photodynamic therapy. In vivo 31P and 1H MRS demonstrated that human cancer xenografts such as melanoma, breast, prostate, ovarian and glioma in immunosuppressed mice treated with metabolic modulators exhibit a sustained and tumor-selective decrease in pH, bioenergetics and increase in lactate and subsequent sensitization to chemo- and radiation therapy.

Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma
The MAPK signaling pathway, frequently driven by BRAF mutations, plays a critical role in the most of melanomas. Although BRAF and MEK inhibitors are commonly used to treat these cancers, not all patients respond favorably. As a result, there is a pressing need to identify noninvasive biomarkers that can predict treatment outcomes and guide personalized therapeutic strategies. We employed noninvasive 1H and 31P magnetic resonance spectroscopy to detect early metabolic biomarkers of response in preclinical human melanoma models treated with BRAF and MEK inhibitors. These findings have the potential to aid in the early prediction of therapeutic responses, contributing to more effective and personalized melanoma treatment approaches.

Metabolic Biomarkers of Response of Lymphomas
Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition.
Our results indicate that BTK inhibition in mantle cell lymphoma (MCL) and mTOR inhibition in diffuse large B cell lymphoma (DLBCL) exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

Selected Publications

Gupta PK*, Orlovskiy S, Arias-Mendoza F, Nelson DS, Nath K*: 1H and 31P Magnetic Resonance Spectroscopic Metabolomic Imaging: Assessing Mitogen-Activated Protein Kinase Inhibition in Melanoma Cells 13 (14): 1220,2024 *Corresponding Author.

Nath K*, Gupta PK, Basappa J, Wang S, Sen N, Lobello C, Tomar JS, Shestov AA, Orlovskiy S, Arias-Mendoza F, Rauert-Wunderlich H, Nelson DS, Glickson JD, Wasik MA*: Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition J Transl Med. 22 (1): 622,2024 *Corresponding Author.

Orlovskiy S, Gupta PK, Roman J, Arias-Mendoza F, Nelson DS, Koch CJ, Narayan V, Putt ME and Nath K*: Lonidamine Induced Selective Acidification and De-Energization of Prostate Cancer Xenografts: Enhanced Tumor Response to Radiation Therapy Cancers 16 (1384): 2024 *Corresponding Author.

Gupta PK, Orlovskiy S, Arias-Mendoza F, Nelson DS, Osborne A, Pickup S, Glickson JD, Nath K*: Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma Cancers 16 : 365,2024 *Corresponding Author.

Gupta PK, Orlovskiy S, Roman J, Pickup S, Nelson DS, Glickson JD, Nath K*: pH-dependent structural characteristics of lonidamine: (1)H and (13)C NMR study RSC Adv 13 (29): 19813-19816,2023. *Corresponding Author.

Nath K, Arias-Mendoza F, Xu HN, Gupta PK, Li LZ: Feasibility of non-invasive measurement of tumor NAD(H) by in vivo phosphorus-31 magnetic resonance spectroscopy Adv Exp Med Biol 1395 : 237-242,2022 .

Chawla, S.; Shehu, V.; Gupta, P.K.; Nath, K.; Poptani, H: Physiological Imaging Methods for Evaluating Response to Immunotherapies in Glioblastomas Int. J. Mol. Sci 22 (8): 3867,2021.

Gupta A, Nath K, Bansal N, Kumar M: Role of metabolomics-derived biomarkers to identify renal cell carcinoma: a comprehensive perspective of the past ten years and advancements Expert Review of Molecular Diagnostics 1 : 5-18,2020.

Xu HN, Feng M, Nath K, Nelson DS, Roman J, Zhao H, Lin Z, Glickson JD, Li LZ: Optical Redox Imaging of Lonidamine Treatment Response of Melanoma Cells and Xenografts Molecular imaging and biology 21 (3): 426-435,2019.

*Nath K, Roman J, Nelson DS, Guo L, Lee SC, Orlovskiy S, Muriuki K, Heitjan DF, Leeper DB, Blair IA, Putt ME, Glickson JD: Effect of Differences in Metabolic Activity of Melanoma Models on Response to Lonidamine plus Doxorubicin Scientific reports 8 (1): 14654,2018 *Corresponding Author.

Academic Contact Information

Perelman School of Medicine at the University of Pennsylvania
Department of Radiology
Laboratory of Molecular Imaging
B6 Blockley Hall
423 Guardian Drive
Philadelphia, PA 19104
Phone: 215-514-9179