Nithya Krishnamurthy - Academia.edu (original) (raw)

Papers by Nithya Krishnamurthy

Journal of Vascular Surgery

Journal of Vascular Surgery: Venous and Lymphatic Disorders

Cancer immunology research, 2021

Immune responses have been successfully reactivated in cancer by targeting inhibitory receptors s... more Immune responses have been successfully reactivated in cancer by targeting inhibitory receptors such as PD-1 on exhausted T cells to block immune checkpoints. Many patients do not respond, however, and a key challenge in immuno-oncology is to identify and understand new immune-regulatory targets to increase response rates. One other co-inhibitory receptor in T cells is TIM3, which – like PD-1 – is upregulated on exhausted T cells in the tumor microenvironment. TIM3 belongs to a family of phosphatidylserine (PS) receptors with well-documented roles in efferocytosis by phagocytes. However, the role of PS in regulating TIM3 remains unclear. Previous studies have shown that TIM3 can variously enhance or inhibit T cell signaling, though exactly how TIM3 accomplishes this range of activity is unknown. We therefore investigated how TIM3 levels modulate T cell signaling, and how PS in turn influences TIM3 activity. We found that TIM3 promoted T cell activity in a Jurkat T cell model when ex...

Biochemical Journal, 2021

Co-signaling receptors for the T cell receptor (TCR) are important therapeutic targets, with bloc... more Co-signaling receptors for the T cell receptor (TCR) are important therapeutic targets, with blockade of co-inhibitory receptors such as PD-1 now central in immuno-oncology. Advancing additional therapeutic immune modulation approaches requires understanding ligand regulation of other co-signaling receptors. One poorly understood potential therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which of TIM-3's several proposed regulatory ligands is/are relevant for signaling is unclear, and different studies have reported TIM-3 as a co-inhibitory or co-stimulatory receptor in T cells. Here, we show that TIM-3 promotes NF-κB signaling and IL-2 secretion following TCR stimulation in Jurkat cells, and that this activity is regulated by binding to phosphatidylserine (PS). TIM-3 signaling is stimulated by PS exposed constitutively in cultured Jurkat cells, and can be blocked by mutating the PS-binding site or by occluding this site with an antibody. We als...

bioRxiv, 2021

Co-signaling receptors for the T cell receptor are important therapeutic targets, with blocking c... more Co-signaling receptors for the T cell receptor are important therapeutic targets, with blocking co-inhibitory receptors such as PD-1 now central in immuno-oncology. Advancing additional therapeutic immune modulation approaches requires understanding ligand regulation of other co-signaling receptors. One poorly understood therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which ligands are relevant for TIM-3 signaling is unclear, and different studies have reported it as co-inhibitory or co-stimulatory. Here, we show that TIM-3 promotes NF-κB signaling and IL-2 secretion following T cell receptor stimulation in Jurkat cells, and is regulated by phosphatidylserine (PS) binding. TIM-3 signaling is stimulated by PS exposed constitutively in cultured Jurkat cells, and can be blocked by mutating the PS-binding site or by occluding this site with an antibody. We also find that TIM-3 signaling alters CD28 phosphorylation. Our findings help clarify conflicting...

European Journal of Cancer, 2021

BACKGROUND STK11 is an important tumour suppressor gene reported to confer immunotherapy resistan... more BACKGROUND STK11 is an important tumour suppressor gene reported to confer immunotherapy resistance in non-small-cell lung cancers (NSCLC) especially in the presence of KRAS co-alterations. METHODS This study analysed 4446 patients for whom next-generation sequencing of tissue and/or circulating tumour DNA (ctDNA) had been performed. RESULTS Overall, 60 of 4446 tumours (1.35%) harboured STK11 alterations. STK11 alterations were associated with shorter median time to progression and overall survival (OS) across cancers from diagnosis: 6.4 months (5.1-7.9) versus 12 months (11.7-12.3; p = 0.001); and 20.5 (17.4-23.5) versus 29.1 (26.9-31.3; p = 0.03), respectively (pan-cancer). Pan-cancers, the median progression-free survival (PFS; 95% CI) for first-line therapy (regardless of treatment type) for those with co-altered STK11 and KRAS (N = 27; versus STK11-altered and KRAS wild type [N = 33]), was significantly shorter (3 [1.3-4.7] versus 10 [4.9-15.7] months, p < 0.0005, p multivariate, 0.06); the median OS also was also shorter (p multivariate = 0.02). In pan-cancer patients treated with checkpoint blockade, STK11 and KRAS co-altered versus STK11-altered/KRAS wild type had a shorter median PFS and trend toward shorter OS (p = 0.04 and p = 0.06, respectively). In contrast, in examining STK11-altered versus wild-type pan-cancer patients treated with checkpoint blockade immunotherapy, the two groups showed no difference in outcome (PFS [p = 0.4]; OS [p = 0.7]); STK11-altered versus wild-type lung cancer patients also did not fare worse on immunotherapy. CONCLUSIONS Across cancers, STK11 alterations correlated with a poor prognosis regardless of therapy. However, STK11 alterations alone did not associate with inferior immunotherapy outcome in the pan-cancer setting or in NSCLC. Pan-cancer patients with co-altered STK11/KRAS did worse, regardless of treatment type.

Background: Despite enthusiasm on the role of repurposing in drug development, enhanced by the Co... more Background: Despite enthusiasm on the role of repurposing in drug development, enhanced by the Covid-19 pandemic with the FDA granting emergency use authorization of several repurposed drugs to treat Covid-19, there remain knowledge gaps on why pharmaceutical companies abandon the development of promising drug candidates as well as facilitators and barriers to moving them back into development, a process often referred to as drug repurposing. Method: This systematic literature review used a combination of controlled vocabulary and free text terms related to the de-prioritization, shelving, abandonment and repurposing of promising experimental drugs unapproved by the FDA for any indication, to search ABI/Informa, Academic Search Premier, Business Source Complete, Cochrane Library, EconLit, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases. The main outcomes of interest were the characteristics and reasons for the phenomenon of com...

Journal for ImmunoTherapy of Cancer, 2020

BackgroundImmune checkpoint blockade has proven effective in targeting exhausted T-cells to react... more BackgroundImmune checkpoint blockade has proven effective in targeting exhausted T-cells to reactivate the immune system against cancer. However, the majority of patients fail to respond to currently available therapies, which primarily target PD-1. Thus, a key challenge for checkpoint blockade therapy is to identify and understand new therapeutic targets. Another immune checkpoint receptor is TIM-3, which – like PD-1 – is expressed on exhausted T-cells in the tumor microenvironment.1, 2 TIM-3 belongs to a family of phosphatidylserine (PS) receptors, including TIM-1 and TIM-4, which have well-documented roles in the engulfment of apoptotic cells by phagocytes.3 However, the role of PS in regulating TIM-3 function is less clear. We therefore investigated how TIM-3 modulates T-cell signaling and how PS influences TIM-3 activity, with the ultimate goal of improving the translation of candidate TIM-3 therapies to the clinic.MethodsSurface plasmon resonance (SPR) was used to quantify the...

Journal of Cancer Metastasis and Treatment, 2020

The rapid advances in the understanding of oncogenic process and the maturation of affordable pre... more The rapid advances in the understanding of oncogenic process and the maturation of affordable precision diagnostic tools have enabled the development of targeted therapeutic agents, such as those targeting BCR-ABL, epithelial growth factor receptor L858R, EML4-anaplastic lymphoma kinase, and BRAF V600E, to treat cancers that harbor specific molecular alterations. Traditionally, each targeted drug has been developed for a particular tumor type where such alteration is most frequently found. Recently, the widespread adoption of next generation sequencing has led to an increase in the identification of rare and ultra-rare alterations, and, in some cases, the same rare alterations are found across multiple tumor types. The rarity of these alterations makes clinical trials traditionally designed for specific tumor types infeasible. As a result, tissue-agnostic trials have been developed to study the efficacy of these treatments and increase patient access. This review summarizes current successful cases of tissue-agnostic development, such as drugs targeting tropomyosin receptor kinase fusions, and proposes the next wave of potential tissue-agnostic targets, including fusions of ROS1 , anaplastic lymphoma kinase, fibroblast growth factor receptor, and rearranged during transfection. In addition, the advantages and the challenges of such approach are discussed in the context of clinical development and approval.

Journal of Clinical Oncology, 2017

11511 Background: Carcinoma of unknown primary (CUP) is a rare, difficult-to-treat malignancy. To... more 11511 Background: Carcinoma of unknown primary (CUP) is a rare, difficult-to-treat malignancy. To further understand the genomic landscape of CUP, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from patient plasma was performed. To our knowledge, this is the largest cohort of patients with CUP interrogated by liquid biopsy. Methods: We evaluated the molecular alterations of 442 patients with CUP using clinical-grade NGS of ctDNA isolated from patient plasma. The test detects single nucleotide variants in 54-70 genes, as well as copy number amplifications, fusions and indels in selected genes. Results: Eighty percent of patients (353/442) had ctDNA alterations with 66% (290/442) harboring at least one characterized alteration; 43.9% (194/442) ≥ 2 characterized alterations. TP53-associated genes were most commonly altered (37.8% [167/442]) followed by genes involved in the MAPK pathway (31.2% [138/442]), PI3K signaling (18.1% [80/442]) and the cell cycle machinery (...

Cancer Treatment Reviews, 2018

Cancer, Jan 6, 2017

Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity ha... more Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015. Of the 423 patients, 61 (14.4%) had TERT promoter mutations, and this placed TERT promoter alterations among the most prevalent aberrations after tumor protein 53 (TP53; 39%) and KRAS and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) alterations (15% each) in this population. TERT promoter alterations were more frequent in men (P = .031) and were associated with brain cancers (P = .001), skin cancers/melanoma (P = .001), and a higher number of aberrations (P = .0001). A co-alterat...

Cancer Research, 2017

Carcinoma of unknown primary (CUP) is a rare and difficult-totreat malignancy, the management of ... more Carcinoma of unknown primary (CUP) is a rare and difficult-totreat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated 54 to 70 genes in 442 patients with CUP using targeted clinicalgrade, next-generation sequencing of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66% (290/442) !1 characterized alteration(s), excluding variants of unknown significance. TP53-associated genes were most commonly altered [37.8% (167/442)], followed by genes involved in the MAPK pathway [31.2% (138/442)], PI3K signaling [18.1% (80/442)], and the cell-cycle machinery [10.4% (46/442)]. Among 290 patients harboring characterized alterations, distinct genomic profiles were observed in 87.9% (255/290) of CUP cases, with 99.7% (289/290) exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of noninvasive liquid biopsies in next-generation clinical trials. Cancer Res; 77(16); 4238-46. Ó2017 AACR.

Journal of Clinical Medicine, 2017