Publications by authors named "Vineeth Sukrithan"

12 Publications

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Targeted Inhibition of the E3 Ligase SCF Has Antitumor Activity in -Deficient Human and Mouse Small-Cell Lung Cancer.

Cancer Res 2020 06 7;80(11):2355-2367. Epub 2020 Apr 7.

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York.

The tumor suppressor gene is mutated in highly aggressive tumors including small-cell lung cancer (SCLC), where its loss, along with , is required and sufficient for tumorigenesis. While -mutant cells fail to arrest at G-S in response to cell-cycle restriction point signals, this information has not led to effective strategies to treat -deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in -knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in -deficient cancers, for which there are currently no targeted therapies available. SIGNIFICANCE: There are no effective therapies for SCLC. The identification of an actionable target downstream of , inactivated in SCLC and other advanced tumors, could have a broad impact on its treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272287PMC
June 2020

Differential Efficacy of Anti-VEGF Antibodies Based on Sex and Race in a Diverse Cohort of Advanced Nonsquamous Non-Small Cell Lung Cancer.

Am J Clin Oncol 2020 01;43(1):64-68

Departments of Oncology.

Objectives: Bevacizumab with chemotherapy improved overall survival (OS) in the E4599 trial in metastatic nonsquamous non-small cell lung cancer (NS-NSCLC). A meta-analysis demonstrated an OS benefit with bevacizumab only in a subset of nonwhite patients. We explored the efficacy of antivascular endothelial growth factor antibodies (AVA) in a diverse cohort.

Materials And Methods: Patients with advanced (stage IIIB/IV, American Joint Committee Cancer 7th edition) recurrent or metastatic NS-NSCLC diagnosed January 2006 to December 2017 at a single medical center were included. Survival analysis was performed with log-rank testing of the Kaplan-Meier estimator. Univariate models were constructed, and significant variables, age, sex, race were incorporated into a multivariate Cox proportional hazard model. Data analysis was performed on SAS.

Results: A total of 171 patients, 80 were treated with AVA and 91 were untreated. Median age: 63 years, 55% females, 19% non-Hispanic whites, 44% blacks and 32% Hispanic whites; median 40 pack-years of smoking; 11.7% had sensitizing epidermal growth factor receptor mutations. Patients who received AVA had a survival benefit (26.6 vs. 19 mo, P=0.025). Adjusting for age, sex, race/ethnicity, epidermal growth factor receptor mutations, Eastern Cooperative Oncology Group performance status and number of metastases; AVA therapy was associated with improved OS (adjusted hazard ratio=0.62; P=0.049). In a subgroup analysis, females had survival benefit with AVA (median survival: 29.1 vs. 14.2 mo, log-rank P=0.02) which was significant in the adjusted model (adjusted hazard ratio=0.52; P=0.049).

Conclusions: In a diverse cohort of patients with advanced NS-NSCLC, a survival benefit was confirmed with AVA. The greatest magnitude of benefit was in blacks and non-Hispanic whites. A significant survival benefit was limited to female patients.
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http://dx.doi.org/10.1097/COC.0000000000000628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980725PMC
January 2020

Sequencing therapies in oncogene-driven non-small-cell lung cancer: how to get the best mileage?

Future Oncol 2019 Sep 19;15(25):2899-2904. Epub 2019 Aug 19.

Department of Hematology/Oncology, Monteflore Medical Center/Albert Einstein College of Medicine, 111 E 210th Street, Bronx, NY 10467, USA.

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http://dx.doi.org/10.2217/fon-2019-0103DOI Listing
September 2019

Implementation of a Low-Cost Quality Improvement Intervention Increases Adherence to Cancer Screening Guidelines and Reduces Healthcare Costs at a University Medical Center.

J Cancer Educ 2020 10;35(5):930-936

University of Arizona Cancer Center, Department of Medicine, The University of Arizona, Tucson, AZ, USA.

Adherence to US Preventative Services Task Force (USPSTF) cancer screening guidelines remains considerably lower than the recommendation of the Healthy People 2020 initiative. Patient populations recommended for screening are not screened at an appropriate rate, and populations not recommended for screening are inappropriately screened. Closer adherence to guidelines should improve outcomes and reduce costs, estimated to reach $158 billion/year by 2020. We evaluated whether a use of low-cost educational health maintenance (HM) card by medical residents at a university hospital could impact education and adherence to updated cancer screening guidelines. We also analyzed savings to the healthcare system. Adherence to cervical, breast, and colorectal cancer screening guidelines, defined as percentage that was screened (or not screened) in accordance with the USPSTF guidelines, in clinic visits from December 2012 (n = 336) was compared to those from December 2013 (n = 306) after a quality improvement intervention. Post-intervention, adherence to screening guidelines increased by 40.8% (p < 0.01) for cervical, 33.2% (p < 0.01) for breast, and 20.5% (p < 0.01) for colorectal cancer in average-risk patients. Inappropriate screening was reduced by 26.8% (p < 0.01) for cervical and 32.8% (p < 0.01) for breast cancer. A non-significant 1.1% decrease (p = 0.829) was observed for colorectal cancer. The annual potential savings from avoiding inappropriate screenings were $998,316 (95% CI; $644,484-$1,352,148). We showed a significant absolute increase in USPSTF knowledge of 28.3% irrespective of the house staff level that remained high at 2 years from the educational intervention. The low-cost HM card increased appropriate knowledgeable cancer screening adherence while reducing unnecessary testing and producing substantial savings to the healthcare system.
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http://dx.doi.org/10.1007/s13187-019-01544-zDOI Listing
October 2020

Immune Checkpoint Blockade Is Associated With Durable Responses in Pulmonary Sarcomatoid Carcinoma.

Clin Lung Cancer 2019 05 24;20(3):e242-e246. Epub 2018 Dec 24.

Department of Hematology/Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2018.12.013DOI Listing
May 2019

Emerging drugs for EGFR-mutated non-small cell lung cancer.

Expert Opin Emerg Drugs 2019 03 20;24(1):5-16. Epub 2018 Dec 20.

a Department of Oncology , Montefiore Medical Center/Albert Einstein College of Medicine , Bronx , NY , USA.

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with metastatic non-small-cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, these agents are associated with inevitable treatment resistance. Newer generations of TKIs are under development that may prevent or overcome resistance and enhance intracranial activity. Areas covered: In this review, we will discuss newer generations of EGFR TKIs for EGFR-mutated NSCLC. We will also address resistance mutations and escape pathways associated with these agents such as secondary mutations, downstream signaling, bypass pathways, phenotypic transformation, anti-apoptotic signaling, immune evasion, and angiogenesis. Furthermore, this article encompasses emerging data from combination trials with next-generation TKIs that are being pursued to delay or prevent the occurrence of resistance. Expert opinion: The promise and challenge of precision oncology is encapsulated in the treatment of EGFR-mutated NSCLC with TKIs. Third generation TKIs have shown superior efficacy in the front-line setting and have become standard of care. A better understanding of mechanisms of treatment failure and disease relapse will be required to develop novel therapeutic strategies to further improve patient outcomes in the future.
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http://dx.doi.org/10.1080/14728214.2018.1558203DOI Listing
March 2019

Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/β-Catenin Activation.

Cancer Res 2017 09 6;77(18):4846-4857. Epub 2017 Jul 6.

Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

The bone marrow microenvironment influences malignant hematopoiesis, but how it promotes leukemogenesis has not been elucidated. In addition, the role of the bone marrow stroma in regulating clinical responses to DNA methyltransferase inhibitors (DNMTi) is also poorly understood. In this study, we conducted a DNA methylome analysis of bone marrow-derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands. Stroma derived from 5-azacytidine-treated patients lacked aberrant methylation and DNMTi treatment of primary MDS stroma enhanced its ability to support erythroid differentiation. An integrative expression analysis revealed that the WNT pathway antagonist FRZB was aberrantly hypermethylated and underexpressed in MDS stroma. This result was confirmed in an independent set of sorted, primary MDS-derived mesenchymal cells. We documented a WNT/β-catenin activation signature in CD34 cells from advanced cases of MDS, where it associated with adverse prognosis. Constitutive activation of β-catenin in hematopoietic cells yielded lethal myeloid disease in a NUP98-HOXD13 mouse model of MDS, confirming its role in disease progression. Our results define novel epigenetic changes in the bone marrow microenvironment, which lead to β-catenin activation and disease progression of MDS. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600853PMC
September 2017

Pancreatic Cancer Heralded by Worsening Glycemic Control: A Report of Two Cases.

J Investig Med High Impact Case Rep 2017 Apr-Jun;5(2):2324709617714286. Epub 2017 Jun 8.

Jacobi Medical Center, Bronx, NY, USA.

Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States. Since it is usually diagnosed at an advanced stage, its prognosis remains poor. The initial presentation varies according to the tumor location. The most common presenting signs are weight loss, jaundice, and pain. Several epidemiological, clinical, and experimental studies over the past 2 decades have shown that long-standing diabetes is a modest risk factor for pancreatic cancer. However, new-onset diabetes has also been observed to be an early manifestation of pancreatic cancer. We report 2 cases where worsening glycemic control led to the diagnosis of pancreatic cancer.
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http://dx.doi.org/10.1177/2324709617714286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468763PMC
June 2017

A systematic review finds limited data on measurement properties of instruments measuring outcomes in adult intensive care unit survivors.

J Clin Epidemiol 2017 Feb 16;82:37-46. Epub 2016 Nov 16.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Baltimore, MD 21287, USA; Outcomes After Critical Illness and Surgery (OACIS) Group, Johns Hopkins University School of Medicine, 1830 East Monument Street, Baltimore, MD 21287, USA; Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.

Background And Objective: There is a growing number of studies evaluating the physical, cognitive, mental health, and health-related quality of life (HRQOL) outcomes of adults surviving critical illness. However, there is little consensus on the most appropriate instruments to measure these outcomes. To inform the development of such consensus, we conducted a systematic review of the performance characteristics of instruments measuring physical, cognitive, mental health, and HRQOL outcomes in adult intensive care unit (ICU) survivors.

Methods: We searched PubMed, Embase, PsycInfo, Cumulative Index of Nursing and Allied Health Literature, and The Cochrane Library in March 2015. We also conducted manual searches of reference lists of eligible studies and relevant review articles. Two people independently selected studies, completed data abstraction, and assessed the quality of eligible studies using the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) initiative checklist.

Results: We identified 20 studies which explicitly evaluated measurement properties for 21 different instruments assessing outcomes in ICU survivors. Eleven of the instruments assessed quality of life, with few instruments assessing other domains. Of the nine measurement properties evaluated on the COSMIN checklist, six were assessed in <10% of the evaluations. Overall quality of eligible studies was generally poor to fair based on the COSMIN checklist.

Conclusions: Although an increasing number of studies measure physical, cognitive, mental health, and HRQOL outcomes in adult ICU survivors, data on the measurement properties of such instruments are sparse and generally of poor to fair quality. Empirical analyses evaluating the performance of instruments in adult ICU survivors are needed to advance research in this field.
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http://dx.doi.org/10.1016/j.jclinepi.2016.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325798PMC
February 2017

Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Cancer Res 2016 08 10;76(16):4841-4849. Epub 2016 Jun 10.

Albert Einstein College of Medicine, Bronx , NY.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398415PMC
August 2016

Systemic mastocytosis presenting as cardiac tamponade with CD25(+) pericardial mast cells.

Clin Case Rep 2016 Mar 8;4(3):279-81. Epub 2016 Feb 8.

Division of Hematology and Oncology Albert Einstein College of Medicine 1300 Morris Park Avenue Bronx New York 10461.

In this first-in-literature case, we describe a patient with Systemic mastocytosis presenting with life-threatening cardiac tamponade associated with the presence of aberrant mast cells in the pericardium. Procedures involving surgical incisions through the pericardium in such cases can lead to uncontrolled mast cell degranulation leading to circulatory collapse.
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http://dx.doi.org/10.1002/ccr3.505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771862PMC
March 2016

Updated systematic review identifies substantial number of retention strategies: using more strategies retains more study participants.

J Clin Epidemiol 2015 Dec 10;68(12):1481-7. Epub 2015 Jun 10.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, 1830 East Baltimore Street, Baltimore, MD 21287, USA.

Background And Objective: The retention of participants in studies is important for the validity of research. We updated our prior systematic review (2005) to assess retention strategies for in-person follow-up in health care studies.

Methods: We searched PubMed, Cumulative Index of Nursing and Allied Health Literature, Cochrane Controlled Trials Register, Cochrane Methodology Register, and Embase (August 2013) for English-language reports of studies that described retention strategies for in-person follow-up in health care studies. We abstracted each retention strategy, and two authors independently classified each retention strategy with one of the themes developed in our prior review.

Results: We identified 88 studies (67 newly identified studies), six of which were designed to compare retention strategies, whereas the remainder described retention strategies and retention rates. There were 985 strategies abstracted from the descriptive studies (617 from new studies), with a median (interquartile range) number of strategies per study of 10 (7 to 17) and a median (interquartile range) number of themes per study of 6 (4 to 7). Financial incentives were used in 47 (57%) of the descriptive studies. We classified 28% of the strategies under the theme of "contact and scheduling methods," with 83% of the identified studies using at least one strategy within this theme. The number of strategies used was positively correlated with retention rate (P = 0.027), but the number of themes was not associated with retention rate (P = 0.469).

Conclusion: The number of studies describing retention strategies has substantially increased since our prior review. However, the lack of comparative studies and the heterogeneity in the types of strategies, participant population and study designs, prohibits synthesis to determine the types of cohort retention strategies that were most effective. However, using a larger number of retention strategies, across five or six different themes, appears to retain more study participants.
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http://dx.doi.org/10.1016/j.jclinepi.2015.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658250PMC
December 2015