Babal Kant Jha Laboratory

Research

Ongoing Research

Therapeutic targeting of TET dioxygenase deficiency

Majority of the myeloid malignancies (>95%) are driven by somatic mutations. While somatic mutations drive the oncogenic evolution, they also provide opportunities for targeted therapeutic development. TET2, a DNA-dioxygenase is frequently affected by loss-of-function mutations (TET2MT) in large proportion of myelodysplastic syndrome (MDS), other associated myeloid neoplasms and a prodromal state of clonal hematopoiesis of indeterminate potential (CHIP). Prevalence of CHIP are associated with a higher risk for subsequent development of myeloid neoplasia and cardiovascular disorders. TETs (TET1, TET2 and TET3) are Fe2+ and α-ketoglutarate-(αKG)-dependent DNA-dioxygenases, which progressively oxidize 5-methylcyctosine (5mC), in gene promoter and enhancer mCpG-islands. TET dependent oxidation of 5mC ultimately leads to demethylation of mCpG, a critical step for transcription regulation in hematopoietic stem and progenitor cells (HSPC) that determine cell lineage fate, differentiation, proliferation and survival. HSPC harboring TET2MT expand because of their dysregulated differentiation and proliferation programs. TET2 accounts for >1/2 of DNA demethylase activity in HSPC. In TET2 mutant cells, maintenance of minimal TET function (largely by TET3 and to some extent by TET1) is essential for efficient transcription controlling their hyper proliferation and survival. We derived this conclusion from mutual exclusivity of neomorphic IDH1/2MT associated with the production of a weak broad spectrum dioxygenase inhibitor, 2-hydroxyglutarate (2HG) in patients with TET2MT. Thus our hypothesis is: complete or partial loss of TET2 leave affected cells vulnerable to further TET-dioxygenase inhibition primarily coming from TET3 and TET1 e.g., with TET inhibitors (TETi). Therefore, using iterative structure-guided rational design, synthesis and biochemical testing, we developed TETi lead compounds. Our study provided a proof-of-concept to test the hypothesis that TET-inhibition may lead to selective synthetic lethality in TET-deficient/TET2MT malignant cells and may be a new therapeutic paradigm for TET2MT, IDH1/2 mutant and TET dioxygenase deficient cancers. These observations (PMIDs: 31007843, 30709865, 29795413, 32895473, 33681816, 33509440) established our basic hypothesis that TET-dioxygenase deficiency can be a targetable vulnerability in Myeloid Leukemia other cancers.

Transient and reversible TET inhibition and expansion of stem and progenitor cells

Recently, we established small molecule TET-inhibitors can be used for the expansion of normal hematopoietic stem and progenitor cells while restricting clonal evolution of malignant cells. In this context we discovered that Eltrombopag (Epag) an FDA approved drug for aplastic anemia is a potent TET inhibitor. Based on our analysis of clinical data coupled with biochemical analysis we established that: i) Epag-mediated inhibition of TET-dioxygenase activity is responsible for tri-lineage response in AA via HSC expansion and on the biochemical level decreased 5hmC content and hypermethylation; ii) direct inhibition of TET2, mimicking LOF mutations, is in part responsible for HSC expansion; iii) Inability to inhibit TET2 or/and hypomethylation of target genes is responsible for response failure in some of the patients. The objectives of this ongoing work is to delineate the mechanism of TET2 inhibition by Epag and its impact on normal and malignant HSPCs (https://pubmed.ncbi.nlm.nih.gov/35085104/).

Heightened ER Stress Response as a targetable vulnerability in Multiple myeloma

Excessive synthesis and secretion of immunoglobulins which are highly enriched in intra-molecular disulfide bonds compared to any other cell types, is a unique feature of MM. This function, while not linked to the malignant behavior, renders MM cells a great dependence on ER resident PDIA1 that isomerizes cysteine. PDIA1 possess monopoly for rearranging intra-molecular disulfide bonds of membrane and secreted proteins that enter the ER to attain correct folding. Lack of correct folding leads to unfolded protein response that are critical for the survival for MM cells. Therefore, even a partial inhibition of PDIs, disrupts survival of MM cells and may offer help to improve outcomes of patients with MM. While normal cells, including plasma cells also require PDIs to fold disulfide-bridges-containing membrane and secreted proteins, transient PDI inhibition does not overwhelm their ER stress defense due to lower rate of protein turnover and lack of micro-environmental stressors that add to protein misfolding seen in neoplasia. We hypothesize that PDIA1 inhibitor may constitute a novel class of therapeutics with specific activity in MM. Therefore our Objectives are i) Translate anti-MM PDI inhibiting pharmacophores into a drug for relapse and refractory MM; ii) Optimize pharmacologic and PDI inhibiting properties of CCF642 and second generation drugs to maximize its clinical potential in MM.

In the News

Scientists find new class of drugs that may treat blood, bone marrow cancer | Business-standard.com

Novel class of targeted cancer therapies could treat myeloid leukaemias | Drug Target Review

Selected Publications

Guan Y, Hasipek M, Jiang D, Tiwari AD, Grabowski DR, Pagliuca S, Kongkiatkamon S, Patel B, Singh S, Parker Y, LaFramboise T, Lindner D, Sekeres MA, Mian OY, Saunthararajah Y, Maciejewski JP, Jha BK. Eltrombopag inhibits TET dioxygenase to contribute to hematopoietic stem cell expansion in aplastic anemia. J Clin Invest. 2022 Feb 15;132(4). doi: 10.1172/JCI149856. PubMed PMID: 35085104; PubMed Central PMCID: PMC8843742.

Hasipek M, Grabowski D, Guan Y, Alugubelli RR, Tiwari AD, Gu X, DeAvila GA, Silva AS, Meads MB, Parker Y, Lindner DJ, Saunthararajah Y, Shain KH, Maciejewski JP, Reu FJ, Phillips JG, Jha BK. Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma. Cancers (Basel). 2021 May 28;13(11). doi: 10.3390/cancers13112649. PubMed PMID: 34071205; PubMed Central PMCID: PMC8198550.

Guan Y, Tiwari AD, Phillips JG, Hasipek M, Grabowski DR, Pagliuca S, Gopal P, Kerr CM, Adema V, Radivoyevitch T, Parker Y, Lindner DJ, Meggendorfer M, Abazeed M, Sekeres MA, Mian OY, Haferlach T, Maciejewski JP, Jha BK. A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms. Blood Cancer Discov. 2021 Mar;2(2):146-161. doi: 10.1158/2643-3230.BCD-20-0173. Epub 2020 Dec 7. PubMed PMID: 33681816; PubMed Central PMCID: PMC7935131.

Jha BK, Saunthararajah Y. Epigenetic modifier directed therapeutics to unleash healthy genes in unhealthy cells. Semin Hematol. 2021 Jan;58(1):1-3. doi: 10.1053/j.seminhematol.2020.11.009. Epub 2020 Dec 14. PubMed PMID: 33509437; PubMed Central PMCID: PMC8832995.

Guan Y, Hasipek M, Tiwari AD, Maciejewski JP, Jha BK. TET-dioxygenase deficiency in oncogenesis and its targeting for tumor-selective therapeutics. Semin Hematol. 2021 Jan;58(1):27-34. doi: 10.1053/j.seminhematol.2020.12.002. Epub 2020 Dec 28. PubMed PMID: 33509440; PubMed Central PMCID: PMC7938524.