Shilpee Dutt

Advanced Centre for Treatment, Research and Education in Cancer | ACTREC · Shilpee Lab

Therapy-induced senescence (TIS) in Glioblastoma (GBM) residual disease and escape from TIS account for resistance and recurrence, but the mechanism of TIS manifestation remains obscure. Here, we demonstrate that replication stress (RS) is critical for the induction of TIS in residual cells by employing an in-vitro GBM therapy-resistance cellular m...

Efficient DNA double strand break (DSB) repair is necessary for genomic stability and determines efficacy of DNA damaging cancer therapeutics. Spatiotemporal dynamics and post-translational modifications of repair proteins at DSBs dictate repair efficacy. Here, we identified a non-canonical function of GCN5 in regulating both HR and NHEJ repair pos...

Background Glioblastoma due to recurrence is clinically challenging with 10-15months overall survival. Previously we showed therapy induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate TIS reversal mechanism for potential therapeutic intervention to prevent GBM recurrence. Methods Residual senescent (RS)...

Drug resistance plays a vital role in both cancer treatment and prognosis. Especially, early insights into such drug‐induced resistance in acute myeloid leukemia (AML) can help to improve treatment plans, reduce costs, and bring overall positive outcomes for patients. Raman spectroscopy provides precise biomolecular information and can provide all...

Anthracyclines, topoisomerase 2 enzyme poison that results in DNA damage, are the mainstay of acute myeloid leukemia (AML) treatment. However, acquired resistance to anthracyclines leads to relapse, which currently lacks effective treatment and is the cause of poor survival in AML patients. Therefore, the identification of the mechanisms underlying...

Recurrent glioblastoma is highly aggressive with currently no specific treatment regime. Therefore, to identify novel therapeutic targets for recurrent GBM, we used a cellular model developed in our lab from commercially available cell line U87MG and patient-derived cultures that allows the comparison between radiation naïve (Parent) and recurrent...

Therapy resistance remains the most challenging obstacle in cancer treatment. Substantial efforts and evidences have accumulated over decades suggesting not only genetic but non-genomic mechanisms underlying this adaptation of tumor cells. Alterations in epigenome can have a fundamental effect on cellular functions and response to stresses like ant...

Nanotechnology-based drug delivery platforms have shown great potential in overcoming the limitations of conventional therapy for glioblastoma (GBM). However, permeation across the blood-brain barrier (BBB), physiological complexity of the brain, and glioma targeting strategies cannot entirely meet the challenging requirements of distinctive therap...

Glioblastoma multiforme (GBM) is one of the most lethal cancer due to poor diagnosis and rapid resistance developed towards the drug. Genes associated to cancer-related overexpression of proteins, enzymes, and receptors can be suppressed using an RNA silencing technique. This assists in obtaining tumour targetability, resulting in less harm caused...

Spatiotemporal targeting of anti-glioma drugs remains a pressing issue in glioblastoma (GBM) treatment. We challenge this issue by developing a minimally invasive in situ implantable hydrogel implant comprising transferrin-targeted temozolomide-miltefosine nanovesicles in the surgically resected GBM cavity (tumour bed). Injection of the "nanovesicl...

Primary treatment modality for glioblastoma (GBM) post-surgery is radiation therapy. Due to increased DNA damage repair capacity of resistant residual GBM cells, recurrence is inevitable in glioblastoma and unfortunately the recurrent tumours are resistant to the conventional therapy. Here we used our previously described in vitro radiation surviva...

The blood–brain barrier (BBB) and tumor heterogeneity have resulted in abysmally poor clinical outcomes in glioblastoma (GBM) with the standard therapeutic regimen.

Glioblastoma (GBM) has poor median survival due to its resistance to chemo-radiotherapy regimen, resulting in tumor recurrence. Recurrent GBMs currently lack effective treatments. DUSP6 is known to be pro-tumorigenic and is up-regulated in GBM. We show that DUSP6 expression is significantly higher in recurrent GBM patient biopsies (n=11) compared t...

Glioblastoma (GBM) is the most lethal primary brain tumour with a median survival of only 15 months. We have previously demonstrated the generation of an in vitro therapy resistance model that captures the residual resistant (RR) disease cells of GBM post-radiation. We also reported the proteomic landscape of parent, residual, and relapse cells usi...

Objective: This hypothesis-driven narrative review aims to explore the evidence for the fundamental process of cell fusion between normal, but different, cell types in the genesis of a cancer cell. Background: Finding out how a cancer is born must remain a top priority as this will allow us the opportunity to understand the disease before it acq...

Background Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) have poor overall survival. Underlying mechanisms have not been fully clarified. This presents an opportunity for precision-oncology for which we systematically analysed publicly-available PDAC transcriptome data. Methods PDAC TCGA RNASeq data were used. Analys...

Senescence is a tumor suppressor phenomenon. We have earlier shown that therapy induced senescence in residual disease glioblastoma (GBM) cells can reverse leading to relapse. Here we demonstrate that ciprofloxacin induced senescence in glioma-derived cell lines and primary cultures defined by β-gal positivity, SASP release, giant-cell formation, h...

Alteration in metabolic repertoire is associated with resistance phenotype. Although a common phenotype, not much efforts have been undertaken to design effective strategies to target the metabolic drift in cancerous cells with drug resistant properties. Here, we identified that drug resistant AML cell line HL-60/MX2 did not follow classical Warbur...

Several non‐invasive Raman spectroscopy‐based assays have been reported for rapid and sensitive detection of pathogens. We developed a novel statistical model for the detection of RNA viruses in saliva, based on an unbiased selection of a set of 65 Raman spectral features that mostly attribute to the RNA moieties, with a prediction accuracy of 91.6...

Glioblastoma (GBM) is the most common primary brain tumor and is highly aggressive with a median survival of 15 months. We have previously shown that residual cells of GBM form multinucleated giant cells (MNGCs) showing a senescent phenotype, but eventually escape from therapy induced senescence (TIS), resulting in GBM recurrence. Here we demonstra...

Early diagnosis of SARS-CoV-2 infected patients is essential to control the dynamics of the COVID-19 pandemic. We develop a rapid and accurate one-step multiplex TaqMan probe-based real-time RT-PCR assay, along with a computational tool to systematically analyse the data. Our assay could detect to a limit of 15 copies of SARS-CoV-2 transcripts—base...

Background: Residual disease of glioblastoma (GBM) causes recurrence. However, targeting residual cells have failed due to their inaccessibility and our lack of understanding their survival mechanisms to radiation therapy. Here we deciphered residual cell specific survival mechanism essential for GBM relapse. Methods: Therapy Resistant Residual...

Corona Virus Disease (COVID-19) caused by novel SARS-CoV-2 has spread like a wildfire, causing respiratory distress in humans at an alarming rate since its inception at Wuhan, China in December 2019. The mortality rate is 2-3%, causing more complications in elderly people, males with pre-existing medical conditions like diabetes, asthma, cardiac an...

Background HER-(human epidermal growth factor receptor 2) gene amplification and protein overexpression are important predictive, prognosis markers, and therapeutic target for breast cancer, emphasizing the importance of categorizing patients into HER2 positive and negative. However, from immunohistochemistry scores, 2% patients are neither HER2 +...

Introduction: There is paucity of data from India about the outcomes of patients with various hematological malignancies. Since its formation in 2009, the adult hematolymphoid disease management group of the Tata Memorial Centre is dedicated to the treatment of hematological malignancies alone. In this report, we present the outcomes of patients tr...

Conjugation of D-glucosamine with lipophilic moiety can ease its application in surface modification of liposomes. Interestingly, although D-glucosamine is safe, studies have shed light on “toxic effect” of its conjugates on cancer cells and highlighted its application in targeting glioma. However, understanding the safety of such conjugates for lo...

To understand the molecular mechanisms underlying disease recurrence in glioblastoma (GBM), we have recapitulated the clincal scenario of therapy resistance in cellular models established from primary patient samples and orthotopic mouse models developed by intracranial injections of GBM cell lines expressing luciferase. Using these models, we have...

System xc− (Sxc−), a cystine‐glutamate antiporter, is established as an interesting target for the treatment of several pathologies including epileptic seizures, glioma, neurodegenerative diseases, and multiple sclerosis. Erastin, sorafenib, and sulfasalazine (SSZ) are a few of the established inhibitors of Sxc−. However, its pharmacological inhibi...

The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho‐proteome array profiling indicates ERBB2 alterations in 40% early‐stage rare gallbladder tumors, among an ethni...

Cytogenetic-based subjective prognostication of acute myeloid leukemia (AML) patients is a cumbersome process. Top scoring pair (TSP)-based decision tree using a robust analytical algorithm with statistical rigor offers a promising alternative. We describe CytoPred as a 7-gene pair signature based on the analysis of 2547 AML patient sample gene exp...

Purpose Previously we have shown, using a primary glioblastoma (GBM) cell model, that a subpopulation of innately radiation resistant (RR) GBM cells survive radiotherapy and form multinucleated and giant cells (MNGCs) by homotypic fusions. We also showed that MNGCs may cause relapse. Here, we set out to explore whether molecular characteristics of...

Preoperative progesterone intervention has been shown to confer a survival benefit to breast cancer patients independently of their progesterone receptor (PR) status. This observation raises the question how progesterone affects the outcome of PR-negative cancer. Here, using microarray and RNA-Seq-based gene expression profiling and ChIP-Seq analys...

Therapy resistance and recurrence in Glioblastoma is due to the presence of residual radiation resistant cells. However, because of their inaccessibility from patient biopsies, the molecular mechanisms driving their survival remain unexplored. Residual Radiation Resistant (RR) and Relapse (R) cells were captured using cellular radiation resistant m...

Leukemia is majorly treated by topoisomerase inhibitors that induce DNA double strand breaks (DSB) resulting in cell death. Consequently, modulation of DSB repair pathway renders leukemic cells resistant to therapy. Since we do not fully understand the regulation of DSB repair acquired by resistant cells, targeting these cells has been a challenge....

Introduction: There is paucity of data from India about the outcomes of patients with various hematological malignancies. Since its formation in 2009, the adult hematolymphoid disease management group of the Tata Memorial Centre is dedicated to the treatment of hematological malignancies alone. In this report, we present the outcomes of patients t...

Introduction: Gallbladder cancer is relatively a rare lethal malignancy with dismal prognosis. While in India there is high incidence (3.9-8.6/1, 00,000) with majority of patients having advanced disease. Recent developments in next generation sequencing technologies have enabled the discovery of new molecular therapeutic targets in many human canc...

Introduction- Resistance to therapeutics targeting topoisomerase 2 is a major problem in the treatment of leukemia. Cells which survive and give rise to relapsed leukemia are known to modulate different pathways like downregulation of drug target, reduced drug accumulation, and improved DNA repair; ultimately leading to survival of drug resistant c...

INTRODUCTION Glioblastoma resistance and recurrence is attributed to the presence of innately Radiation Resistant (RR) cells present in the heterogeneous parent tumour. However, targeting these cells has been impossible due to inaccessibility of these cells. METHODOLOGY We therefore recapitulated clinical scenario of resistance in a cellular model...

Bystander cells of the tumor microenvironment show evidence of DNA damage and inflammation that can lead to their oncogenic transformation. Mediator(s) of cell–cell communication that brings about these pro-oncogenic pathologies has not been identified. We show here that cell-free chromatin (cfCh) released from dying cancer cells are the key mediat...

Senescence is a phenomenon of 'end of cells replicative capacity', characterized by irreversible cell cycle arrest which in the context of cancer, will contain the growth of tumour. Hence possibility of using pro-senescence therapies for cancer therapeutics has generated substantial interest. In this regards there are several reports showing that s...

Glioblastoma (GBM), also known as grade IV astro-cytoma, is the most malignant and lethal glial tumours, accounting for about 30% of the adult brain tumours. Due to its highly invasive nature and intrinsic resistance to the existing treatment modalities, the median survival time of GBM patients has not improved beyond 14.6 months. Animal models sim...

Background: Notch pathway plays a complex role depending on cellular contexts: promotes stem cell maintenance or induces terminal differentiation in potential cancer-initiating cells; acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. Here, we present a novel...

An inability to discern resistant cells from bulk tumour cell population contributes to poor prognosis in Glioblastoma. Here, we compared parent and recurrent cells generated from patient derived primary cultures and cell lines to identify their unique molecular hallmarks. Although morphologically similar, parent and recurrent cells from different...

Background: Glioblastoma is the most invasive type of glial tumors, with 14.6 months median survival time of patients contributed partly due to inherent resistance to conventional therapies. Using an in vitro radiation survival models from glioblastoma cell lines and primary patient samples, we had previously shown that a subset of cells, termed as...

Background: After induction therapy minimal residual (MRD) cells progress to more aggressive state of recurrent leukemia, which is a major problem in treating leukemia. Therefore, we hypothesize that elimination of MRD during early stages of resistance would abrogate relapse. Methods: We modeled acquire resistance of leukemia in vitro that help us...

Background: After induction therapy minimal residual (MRD) cells progress to more aggressive state of recurrent leukemia, which is a major problem in treating leukemia. Therefore, we hypothesize that elimination of MRD during early stages of resistance would abrogate relapse. Methods: We modeled acquire resistance of leukemia in vitro that help us...

Background: Innately Radiation Resistant (RR)-the major cause of Glioblastoma recurrence have not been possible to target due to incomplete understanding of their biology. Therefore, to gain access to RR cells we developed an in vitro radiation resistance model from primary patient samples and GBM cell lines. The innately radiation resistant cells...

Resistance to chemotherapy is a major challenge in the field of leukemia. Since, cancer cells can acquire resistance to DNA damage based therapy by modulating DNA Damage Repair (DDR) pathways, an in-depth understanding of DDR is important for novel drug discoveries. Hence, to understand relation between DDR and resistance we used doxorubicin resist...

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA In this study, we address the fundamental issue of radiation resistance in Glioblastoma Multiforme (GBM) a highly malignant form of brain tumor. However, because of the unavailability of multiple biopsies of GBM patients after treatment, we are limited in our understa...

Understanding of molecular events underlying resistance and relapse in Glioblastoma (GBM) is hampered due to lack of accessibility to resistant cells from patients undergone therapy. Therefore, we mimicked clinical scenario in an in vitro cellular model developed from five Glioblastoma grade IV primary patient samples and two cell lines. We show th...

Metastasis-associated gene or metastasis tumor antigen 1 (MTA1) is a new member of cancer progression-related gene family. It was first identified in rat mammary adenocarcinoma and later recognized as an important constituent of nucleosomal remodeling complex (NuRD), displaying dual regulatory functions as a co-repressor and co-activator for a larg...

Hemoglobin is the major biosynthetic product of developing erythroid cells. Assembly of hemoglobin requires the balanced production of globin proteins and the oxygen-carrying heme moiety. The heme-regulated inhibitor kinase (HRI) participates in this process by phosphorylating eIF2α and inhibiting the translation of globin proteins when levels of f...

Corticosteroids and lenalidomide decrease red blood cell transfusion dependence in patients with Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome (MDS), respectively. We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Bo...

Peanut agglutinin-binding disaccharides and chondroitin sulfate mark transient mesenchymal barriers to advancing motor and sensory axons innervating the hindlimbs during chick development. Here we show that the vast majority of these carbohydrates are at the critical stage and location attached to the versican splice variants V0 and V1. We reveal t...

Haploinsufficiency for ribosomal protein genes has been implicated in the pathophysiology of Diamond-Blackfan anemia (DBA) and the 5q-syndrome, a subtype of myelodysplastic syndrome. The p53 pathway is activated by ribosome dysfunction, but the molecular basis for selective impairment of the erythroid lineage in disorders of ribosome function has n...

948 Haploinsufficiency for the ribosomal protein genes RPS14 and RPS19 have been implicated in the erythroid defect in the 5q- syndrome and Diamond Blackfan Anemia, respectively. However, the mechanism by which defective ribosome biogenesis causes erythroid failure is unknown. In this study, we found that shRNA mediated knockdown of RPS14 or RPS19...

1092 Poster Board I-114 Lenalidomide, a derivative of thalidomide, induces erythroid responses in patients with myelodysplastic syndrome while dexamethasone induces erythroid responses in patients with Diamond Blackfan anemia. In vitro, both lenalidomide and dexamethasone have been shown to stimulate erythropoiesis. In the present study, we explore...

3958 Poster Board III-894 Although the BBAP E3 ligase and its binding partner, BAL, are overexpressed in chemotherapy-resistant diffuse large B-cell lymphomas (DLBCLs), the role of these proteins in response to DNA damage remains undefined. The BBAP and BAL1 genes are located on chromosome 3q21 in a head-to-head orientation and regulated by the sam...

Although the BBAP E3 ligase and its binding partner BAL are overexpressed in chemotherapy-resistant lymphomas, the role of these proteins in DNA damage responses remains undefined. Because BAL proteins modulate promoter-coupled transcription and contain structural motifs associated with chromatin remodeling and DNA repair, we reasoned that the BBAP...

During differentiation, B cells receive signals by antigen through the B-cell receptor (BCR) and signals that induce isotype switching. We sought to investigate the effects of BCR ligation on isotype switching. Naive B cells from BALB/c mice were stimulated with LPS plus IL-4 alone or plus anti-IgM (0.1-10 mug/mL). IgE and IgG1 levels in supernatan...

p53-Binding protein 1 (53BP1) encodes a critical checkpoint protein that localizes to sites of DNA double-strand breaks (DSBs) and participates in DSB repair. Mice that are 53bp1 deficient or hemizygous have an increased incidence of lymphoid malignancies. However, 53BP1 abnormalities in primary human tumors have not been described. By combining hi...

The maintenance of genomic integrity relies on the cellular response to chromosomal damage from both exogenous (e.g. ionizing radiation) and endogenous (e.g. oxidative stress) sources. Various members of the DNA damage-sensing pathway including ATM, H2AX, 53BP1, and MDC1 are necessary to orchestrate the repair of DNA breaks. B cells undergo several...