Publications by authors named "Prakash Kulkarni"

93 Publications

Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-genetic Heterogeneity in Prostate Cancer Cells.

Entropy (Basel) 2021 Feb 26;23(3). Epub 2021 Feb 26.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.

Non-genetic heterogeneity is emerging as a crucial factor underlying therapy resistance in multiple cancers. However, the design principles of regulatory networks underlying non-genetic heterogeneity in cancer remain poorly understood. Here, we investigate the coupled dynamics of feedback loops involving (a) oscillations in androgen receptor (AR) signaling mediated through an intrinsically disordered protein PAGE4, (b) multistability in epithelial-mesenchymal transition (EMT), and c) Notch-Delta-Jagged signaling mediated cell-cell communication, each of which can generate non-genetic heterogeneity through multistability and/or oscillations. Our results show how different coupling strengths between AR and EMT signaling can lead to monostability, bistability, or oscillations in the levels of AR, as well as propagation of oscillations to EMT dynamics. These results reveal the emergent dynamics of coupled oscillatory and multi-stable systems and unravel mechanisms by which non-genetic heterogeneity in AR levels can be generated, which can act as a barrier to most existing therapies for prostate cancer patients.
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http://dx.doi.org/10.3390/e23030288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996788PMC
February 2021

Quantifying Cancer: More Than Just a Numbers Game.

Trends Cancer 2021 Apr 26;7(4):267-269. Epub 2021 Feb 26.

Trends in Cancer, Cell Press, Cambridge, MA 02139, USA. Electronic address:

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http://dx.doi.org/10.1016/j.trecan.2021.02.002DOI Listing
April 2021

RLIP Depletion Induces Apoptosis Associated with Inhibition of JAK2/STAT3 Signaling in Melanoma Cells.

Carcinogenesis 2021 Feb 24. Epub 2021 Feb 24.

Department of Medical Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center and National Medical Center, Duarte, CA, USA.

The incidence of malignant melanoma, a neoplasm of melanocytic cells, is increasing rapidly. The lymph nodes are often the first site of metastasis and can herald systemic dissemination, which is almost uniformly fatal. RLIP, a multi-specific ATP-dependent transporter that is over-expressed in several types of cancers, plays a central role in cancer cell resistance to radiation and chemotherapy. RLIP appears to be necessary for cancer cell survival because both in-vitro cell culture and in-vivo animal tumor studies show that the depletion or inhibition of RLIP causes selective toxicity to malignant cells. RLIP depletion/inhibition triggers apoptosis in cancer cells by inducing the accumulation of endogenously formed glutathione-conjugates. In our in-vivo studies, we administered RLIP antibodies or antisense oligonucleotides to mice bearing subcutaneous xenografts of SKMEL2 and SKMEL5 melanoma cells and demonstrated that both treatments caused significant xenograft regression with no apparent toxic effects. Anti-RLIP antibodies and antisense, which respectively inhibit RLIP-mediated transport and deplete RLIP expression, showed similar tumor regressing activities, indicating that the inhibition of RLIP transport activity at the cell surface is sufficient to achieve anti-tumor activity. Furthermore, RLIP antisense treatment reduced levels of RLIP, pSTAT3, pJAK2, pSrc, Mcl-1, and Bcl2, as well as CDK4 and cyclin B1, and increased levels of Bax and pAMPK. These studies indicate that RLIP serves as a key effector in the survival of melanoma cells and is a valid target for cancer therapy. Overall, compounds that inhibit, deplete, or downregulate RLIP will function as wide-spectrum agents to treat melanoma, independent of common signaling pathway mutations.
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http://dx.doi.org/10.1093/carcin/bgab016DOI Listing
February 2021

Group Behavior and Emergence of Cancer Drug Resistance.

Trends Cancer 2021 Apr 20;7(4):323-334. Epub 2021 Feb 20.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA. Electronic address:

Drug resistance is a major impediment in cancer. Although it is generally thought that acquired drug resistance is due to genetic mutations, emerging evidence indicates that nongenetic mechanisms also play an important role. Resistance emerges through a complex interplay of clonal groups within a heterogeneous tumor and the surrounding microenvironment. Traits such as phenotypic plasticity, intercellular communication, and adaptive stress response, act in concert to ensure survival of intermediate reversible phenotypes, until permanent, resistant clones can emerge. Understanding the role of group behavior, and the underlying nongenetic mechanisms, can lead to more efficacious treatment designs and minimize or delay emergence of resistance.
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http://dx.doi.org/10.1016/j.trecan.2021.01.009DOI Listing
April 2021

Prevention of mammary carcinogenesis in MMTV-neu mice by targeting RLIP.

Mol Carcinog 2021 03 5;60(3):213-223. Epub 2021 Feb 5.

Departments of Medical Oncology, City of Hope Comprehensive Cancer Center and National Medical Center, Duarte, California, USA.

The overexpression and amplification of the protooncogene neu (ERBB2) play an important role in the development of aggressive breast cancer (BC) in humans. Ral-interacting protein (RLIP), a modular stress-response protein with pleiotropic functions, is overexpressed in several types of cancer, including BC. Here, we show that blocking RLIP attenuates the deleterious effects caused by the loss of the tumor suppressor p53 and inhibits the growth of human BC both in vitro and in vivo in MMTV-neu mice. In addition, we show that treatment with the diet-derived, RLIP-targeting chemotherapeutic 2'-hydroxyflavanone (2HF), alone or in combination with RLIP-specific antisense RNA or antibodies, significantly reduced the cumulative incidence and/or burden of mammary hyperplasia and carcinoma in MMTV-neu mice. 2HF treatment correlated with reduced tumor cell proliferation and increased apoptosis, and the average number of Ki67-positive (proliferating) cells was significantly lower in the tumors of 2HF-treated mice than in the tumors of control mice. Furthermore, targeting RLIP also resulted in the overexpression of E-cadherin and the infiltration of CD3 T cells into mammary tumors. Taken together, these results underscore the translational potential of RLIP-targeting agents and provide a strong rationale to validate them in the clinic.
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http://dx.doi.org/10.1002/mc.23285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952002PMC
March 2021

Co-stimulatory and co-inhibitory immune markers in solid tumors with alterations.

Future Sci OA 2020 Nov 25;7(2):FSO662. Epub 2020 Nov 25.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

The implication of alterations in solid tumors and the immune microenvironment remains elusive. Formalin-fixed, paraffin-embedded samples of 21 patients with solid tumors harboring alterations were used for immunohistochemical staining. Extracted RNA was analyzed with the NanoString nCounter human PanCancer immune profiling panel (NanoString Technologies, Inc., WA, USA). Patients were diagnosed with lung (n = 10), breast (n = 5), genitourinary (n = 3) or colorectal cancer (n = 3). Eleven had a missense mutation, four had an exon 14 splice site mutation and six had amplification. , , , , , and genes were significantly differentially expressed in -altered cancers. alterations may have a role in various solid tumors as potential therapeutic targets and combination therapy candidates with immune checkpoint inhibitors.
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http://dx.doi.org/10.2144/fsoa-2020-0159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787173PMC
November 2020

Integrating Academic and Community Cancer Care and Research through Multidisciplinary Oncology Pathways for Value-Based Care: A Review and the City of Hope Experience.

J Clin Med 2021 Jan 7;10(2). Epub 2021 Jan 7.

Department of Clinical Informatics, City of Hope, Duarte, CA 91010, USA.

As the US transitions from volume- to value-based cancer care, many cancer centers and community groups have joined to share resources to deliver measurable, high-quality cancer care and clinical research with the associated high patient satisfaction, provider satisfaction, and practice health at optimal costs that are the hallmarks of value-based care. Multidisciplinary oncology care pathways are essential components of value-based care and their payment metrics. Oncology pathways are evidence-based, standardized but personalizable care plans to guide cancer care. Pathways have been developed and studied for the major medical, surgical, radiation, and supportive oncology disciplines to support decision-making, streamline care, and optimize outcomes. Implementing multidisciplinary oncology pathways can facilitate comprehensive care plans for each cancer patient throughout their cancer journey and across large multisite delivery systems. Outcomes from the delivered pathway-based care can then be evaluated against individual and population benchmarks. The complexity of adoption, implementation, and assessment of multidisciplinary oncology pathways, however, presents many challenges. We review the development and components of value-based cancer care and detail City of Hope's (COH) academic and community-team-based approaches for implementing multidisciplinary pathways. We also describe supportive components with available results towards enterprise-wide value-based care delivery.
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http://dx.doi.org/10.3390/jcm10020188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825796PMC
January 2021

Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas.

iScience 2020 Nov 16;23(11):101692. Epub 2020 Oct 16.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA.

The tyrosine kinase receptor ephrin receptor A2 (EPHA2) is overexpressed in lung (LSCC) and head and neck (HNSCC) squamous cell carcinomas. Although EPHA2 can inhibit tumorigenesis in a ligand-dependent fashion via phosphorylation of Y588 and Y772, it can promote tumorigenesis in a ligand-independent manner via phosphorylation of S897. Here, we show that EPHA2 and Roundabout Guidance Receptor 1 (ROBO1) interact to form a functional heterodimer. Furthermore, we show that the ROBO1 ligand Slit Guidance Ligand 2 (SLIT2) and ensartinib, an inhibitor of EPHA2, can attenuate growth of HNSCC cells and act synergistically in LSCC cells. Our results suggest that patients with LSCC and HNSCC may be stratified and treated based on their EPHA2 and ROBO1 expression patterns. Although ~73% of patients with LSCC could benefit from SLIT2+ensartinib treatment, ~41% of patients with HNSCC could be treated with either SLIT2 or ensartinib. Thus, EPHA2 and ROBO1 represent potential LSCC and HNSCC theranostics.
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http://dx.doi.org/10.1016/j.isci.2020.101692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644594PMC
November 2020

Intrinsically Disordered Proteins: Insights from Poincaré, Waddington, and Lamarck.

Authors:
Prakash Kulkarni

Biomolecules 2020 10 28;10(11). Epub 2020 Oct 28.

Department of Medical Oncology and Experimental Therapeutics, City of Hope, National Medical Center, Duarte, CA 91010, USA.

The past quarter-century may justly be referred to as a period analogous to the "Cambrian explosion" in the history of proteins. This period is marked by the appearance of the intrinsically disordered proteins (IDPs) on the scene since their discovery in the mid-1990s. Here, I first reflect on how we accidentally stumbled on these fascinating molecules. Next, I describe our research on the IDPs over the past decade and identify six areas as important for future research in this field. In addition, I draw on discoveries others in the field have made to present a more comprehensive essay. More specifically, I discuss the role of IDPs in two fundamental aspects of life: in phenotypic switching, and in multicellularity that marks one of the major evolutionary transitions. I highlight how serendipity, imagination, and an interdisciplinary approach embodying empirical evidence and theoretical insights from the works of Poincaré, Waddington, and Lamarck, shaped our thinking, and how this led us to propose the MRK hypothesis, a conceptual framework addressing phenotypic switching, the emergence of new traits, and adaptive evolution via nongenetic and IDP conformation-based mechanisms. Finally, I present a perspective on the evolutionary link between phenotypic switching and the origin of multicellularity.
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http://dx.doi.org/10.3390/biom10111490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692701PMC
October 2020

A Non-genetic Mechanism Involving the Integrin β4/Paxillin Axis Contributes to Chemoresistance in Lung Cancer.

iScience 2020 Aug 22;23(9):101496. Epub 2020 Aug 22.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA. Electronic address:

Tumor heterogeneity and cisplatin resistance are major causes of tumor relapse and poor survival. Here, we show that in lung cancer, interaction between paxillin (PXN) and integrin β4 (ITGB4), components of the focal adhesion (FA) complex, contributes to cisplatin resistance. Knocking down PXN and ITGB4 attenuated cell growth and improved cisplatin sensitivity, both in 2D and 3D cultures. PXN and ITGB4 independently regulated expression of several genes. In addition, they also regulated expression of common genes including USP1 and VDAC1, which are required for maintaining genomic stability and mitochondrial function, respectively. Mathematical modeling suggested that bistability could lead to stochastic phenotypic switching between cisplatin-sensitive and resistant states in these cells. Consistently, purified subpopulations of sensitive and resistant cells re-created the mixed parental population when cultured separately. Altogether, these data point to an unexpected role of the FA complex in cisplatin resistance and highlight a novel non-genetic mechanism.
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http://dx.doi.org/10.1016/j.isci.2020.101496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502350PMC
August 2020

Integrating Clinical and Translational Research Networks-Building Team Medicine.

J Clin Med 2020 Sep 15;9(9). Epub 2020 Sep 15.

City of Hope National Medical Center, Duarte, CA 91010, USA.

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http://dx.doi.org/10.3390/jcm9092975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563426PMC
September 2020

Small Cell Lung Cancer from Traditional to Innovative Therapeutics: Building a Comprehensive Network to Optimize Clinical and Translational Research.

J Clin Med 2020 Jul 30;9(8). Epub 2020 Jul 30.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

Small cell lung cancer (SCLC) is an aggressive, complex disease with a distinct biology that contributes to its poor prognosis. Management of SCLC is still widely limited to chemotherapy and radiation therapy, and research recruitment still poses a considerable challenge. Here, we review the current standard of care for SCLC and advances made in utilizing immunotherapy. We also highlight research in the development of targeted therapies and emphasize the importance of a team-based approach to make clinical advances. Building an integrative network between an academic site and community practice sites optimizes biomarker and drug target discovery for managing and treating a difficult disease like SCLC.
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http://dx.doi.org/10.3390/jcm9082433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464169PMC
July 2020

Characterization of RNA-Binding Motif 3 (RBM3) Protein Levels and Nuclear Architecture Changes in Aggressive and Recurrent Prostate Cancer.

Cancer Rep (Hoboken) 2020 Jun 29;3(3):e1237. Epub 2020 Jan 29.

The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: The RNA-binding motif protein 3 (RBM3) has been shown to be up-regulated in several types of cancer, including prostate cancer (PCa), compared to normal tissues. Increased RBM3 nuclear expression has been linked to improved clinical outcomes.

Aims: Given that RBM3 has been hypothesized to play a role in critical nuclear functions such as chromatin remodeling, DNA damage response, and other post-transcriptional processes, we sought to: (1) quantify RBM3 protein levels in archival PCa samples; (2) develop a nuclear morphometric model to determine if measures of RBM3 protein levels and nuclear features could be used to predict disease aggressiveness and biochemical recurrence.

Methods & Results: This study utilized two tissue microarrays (TMAs) stained for RBM3 that included 80 total cases of PCa stratified by Gleason score. A software-mediated image processing algorithm identified RBM3-positive cancerous nuclei in the TMA samples and calculated twenty-two features quantifying RBM3 expression and nuclear architecture. Multivariate logistic regression (MLR) modeling was performed to determine if RBM3 levels and nuclear structural changes could predict PCa aggressiveness and biochemical recurrence (BCR). Leave-one-out cross validation (LOOCV) was used to provide insight on how the predictive capabilities of the feature set might behave with respect to an independent patient cohort to address issues such as model overfitting. RBM3 expression was found to be significantly downregulated in highly aggressive GS ≥ 8 PCa samples compared to other Gleason scores ( < 0.0001) and significantly down-regulated in recurrent PCa samples compared to non-recurrent samples ( = 0.0377). An eleven-feature nuclear morphometric MLR model accurately identified aggressive PCa, yielding a receiver operating characteristic area under the curve (ROC-AUC) of 0.90 ( < 0.0001) in the raw data set and 0.77 (95% CI: 0.83-0.97) for LOOCV testing. The same eleven-feature model was then used to predict recurrence, yielding a ROC-AUC of 0.92 ( = 0.0004) in the raw data set and 0.76 (95% CI: 0.64-0.87) for LOOCV testing.

Conclusions: The RBM3 biomarker alone is a strong prognostic marker for the prediction of aggressive PCa and biochemical recurrence. Further, RBM3 appears to be down-regulated in aggressive and recurrent tumors.
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http://dx.doi.org/10.1002/cnr2.1237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316183PMC
June 2020

Complex Oncological Decision-Making Utilizing Fast-and-Frugal Trees in a Community Setting-Role of Academic and Hybrid Modeling.

J Clin Med 2020 Jun 16;9(6). Epub 2020 Jun 16.

Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA.

Non-small cell lung cancer is a devastating disease and with the advent of targeted therapies and molecular testing, the decision-making process has become complex. While established guidelines and pathways offer some guidance, they are difficult to utilize in a busy community practice and are not always implemented in the community. The rationale of the study was to identify a cohort of patients with lung adenocarcinoma at a City of Hope community site (n = 11) and utilize their case studies to develop a decision-making framework utilizing fast-and-frugal tree (FFT) heuristics. Most patients had stage IV (N = 9, 81.8%) disease at the time of the first consultation. The most common symptoms at initial presentation were cough (N = 5, 45.5%), shortness of breath (N = 3, 27.2%), and weight loss (N = 3, 27.2%). The Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0-1 in all patients in this study. Distribution of molecular drivers among the patients were as follows: EGFR (N = 5, 45.5%), KRAS (N = 2, 18.2%), ALK (N = 2, 18.2%), MET (N = 2, 18.2%), and RET (N = 1, 9.1%). Seven initial FFTs were developed for the various case scenarios, but ultimately the decisions were condensed into one FFT, a molecular stage IV FFT, that arrived at accurate decisions without sacrificing initial information. While these FFT decision trees may seem arbitrary to an experienced oncologist at an academic site, the simplicity of their utility is essential for community practice where patients often do not get molecular testing and are not assigned proper therapy.
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http://dx.doi.org/10.3390/jcm9061884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356888PMC
June 2020

Association of molecular characteristics with survival in advanced non-small cell lung cancer patients treated with checkpoint inhibitors.

Lung Cancer 2020 08 24;146:174-181. Epub 2020 May 24.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA; Division of Medical Oncology, Cedars-Sinai Medical Center, USA. Electronic address:

Objectives: Immune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients.

Materials And Methods: All advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher's exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis.

Results: 346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06-0.59; P < 0.01), EGFR (HR 7.38; 95% CI, 1.15-47.42; P < 0.05), and TET2 (HR 0.15; 95% CI, 0.03-0.90; P < 0.05). The median OS was not reached [NR] for the 12 patients who had genomic alterations (GAs) in TET2 (12/108, 11%) versus (vs) 11.5 months in TET2 negative patients (98/108, 89%). Interestingly, GAs in TET2 and FANCA were mutually exclusive and patients who had GAs in FANCA gene (6%) had shorter OS (5.5 months vs 14.5 months, Log-rank test, P < 0.05).

Conclusions: We described the clinical and molecular features of NSCLC patients treated with ICIs. The association of GAs in TET2 with longer OS and its mutual exclusivity with FANCA GAs were insightful for developing novel therapeutic strategies to improve ICIs outcomes in NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.025DOI Listing
August 2020

Non-Small Cell Lung Cancer from Genomics to Therapeutics: A Framework for Community Practice Integration to Arrive at Personalized Therapy Strategies.

J Clin Med 2020 Jun 15;9(6). Epub 2020 Jun 15.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA 91010, USA.

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, and therapeutic management has advanced with the identification of various key oncogenic mutations that promote lung cancer tumorigenesis. Subsequent studies have developed targeted therapies against these oncogenes in the hope of personalizing therapy based on the molecular genomics of the tumor. This review presents approved treatments against actionable mutations in NSCLC as well as promising targets and therapies. We also discuss the current status of molecular testing practices in community oncology sites that would help to direct oncologists in lung cancer decision-making. We propose a collaborative framework between community practice and academic sites that can help improve the utilization of personalized strategies in the community, through incorporation of increased testing rates, virtual molecular tumor boards, vendor-based oncology clinical pathways, and an academic-type singular electronic health record system.
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http://dx.doi.org/10.3390/jcm9061870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356243PMC
June 2020

Implementing Lung Cancer Screening and Prevention in Academic Centers, Affiliated Network Offices and Collaborating Care Sites.

J Clin Med 2020 Jun 11;9(6). Epub 2020 Jun 11.

City of Hope Medical Center, Duarte, CA 91010, USA.

Lung cancer is one of the deadliest and yet largely preventable neoplasms. Smoking cessation and lung cancer screening are effective yet underutilized lung cancer interventions. City of Hope Medical Center, a National Cancer Institute (NCI)- designated comprehensive cancer center, has 27 community cancer centers and has prioritized tobacco control and lung cancer screening throughout its network. Despite challenges, we are implementing and monitoring the City of Hope Tobacco Control Initiative including 1) a Planning and Implementation Committee; 2) integration of IT, e.g., medical records and clinician notification/prompts to facilitate screening, cessation referral, and digital health, e.g., telehealth and social media; 3) clinician training and endorsing national guidelines; 4) providing clinical champions at all sites for site leadership; 5) Coverage and Payment reform and aids to facilitate patient access and reduce cost barriers; 6) increasing tobacco exposure screening for all patients; 7) smoking cessation intervention and evaluation-patient-centered recommendations for smoking cessation for all current and recent quitters along with including QuitLine referral for current smokers and smoking care-givers; and 8) establishing a Tobacco Registry for advancing science and discoveries including team science for basic, translation and clinical studies. These strategies are intended to inform screening, prevention and treatment research and patient-centered care.
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http://dx.doi.org/10.3390/jcm9061820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356827PMC
June 2020

Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion.

Cancer Cell 2020 07 11;38(1):79-96.e11. Epub 2020 Jun 11.

Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center and Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA. Electronic address:

Fat mass and obesity-associated protein (FTO), an RNA N-methyladenosine (mA) demethylase, plays oncogenic roles in various cancers, presenting an opportunity for the development of effective targeted therapeutics. Here, we report two potent small-molecule FTO inhibitors that exhibit strong anti-tumor effects in multiple types of cancers. We show that genetic depletion and pharmacological inhibition of FTO dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4. FTO inhibition sensitizes leukemia cells to T cell cytotoxicity and overcomes hypomethylating agent-induced immune evasion. Our study demonstrates that FTO plays critical roles in cancer stem cell self-renewal and immune evasion and highlights the broad potential of targeting FTO for cancer therapy.
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http://dx.doi.org/10.1016/j.ccell.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363590PMC
July 2020

Effects of selected deubiquitinating enzyme inhibitors on the proliferation and motility of lung cancer and mesothelioma cell lines.

Int J Oncol 2020 Jul 1;57(1):80-86. Epub 2020 Apr 1.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010‑3000, USA.

The post‑translational modification of proteins by ubiquitinating enzymes plays a central role in a number of cellular functions, such as cell proteolysis, DNA repair, and cell signaling and communication. Deubiquitinating enzymes (DUBs) disassemble ubiquitin chains and remove ubiquitin moieties from proteins. Targeting DUBs in cancer models has revealed an important role for these enzymes in tumorigenesis, and they therefore have emerged as attractive therapeutic targets. In the present study, the effects of three DUB inhibitors, PR‑619, RA‑9 and LDN‑91946, on a non‑small cell lung cancer cell line (A549) and a mesothelioma cell line (H2373) were investigated. PR‑619 significantly inhibited cell adhesion and the proliferation of both cell lines. RA‑9 exerted an inhibitory effect on the adhesion and proliferation of H2373 cells, whereas it had no effect on A549 cells. Notably, however, while PR‑619 attenuated the proliferation of both cell lines, it exerted an opposite effect on cell motility; in the case of A549 cells, there was a significant increase in cell motility, while for the H2373 cells, there was a significant decrease. Furthermore, protein phosphorylation kinetic analyses revealed that the effects were cell line‑specific. In H2373 cells, the phosphorylation of only one peptide corresponding to the P85A protein was significantly affected, and while LDN‑91946 treatment increased phosphorylation, treatment with RA‑9 or PR‑619 decreased its phosphorylation compared to the DMSO control. By contrast, in the case of A549 cells, the phosphorylation of 21 peptides was significantly affected by the same compounds. In light of the potential for the negative side‑effects of DUB inhibition, such as increased cancer cell motility, the data presented herein underscore the dire need for the development of specific DUB inhibitors and to elucidate the individual role of DUB family members in cancer biology before they can be specifically pharmacologically targeted.
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http://dx.doi.org/10.3892/ijo.2020.5034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252467PMC
July 2020

FAK-targeted and combination therapies for the treatment of cancer: an overview of phase I and II clinical trials.

Expert Opin Investig Drugs 2020 Apr 19;29(4):399-409. Epub 2020 Mar 19.

Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.

: Focal adhesion kinase (FAK) is a promising target for the treatment of solid tumors because its expression has been linked to tumor progression, invasion, and drug resistance. Several FAK inhibitors have been developed and tested for efficacy in treating advanced cancers. Four FAK inhibitors have shown promising preclinical data and have advanced to clinical development in solid tumors.: This article provides a systematic review on FAK inhibitors that have been tested or are currently in clinical trials in advanced solid tumors. We discuss the efficacy of GSK2256098, PF-00562271, VS-6063, and BI 853520 in the preclinical setting and summarize the results of phase I/II clinical trials evaluating these compounds.: The FAK inhibitors examined in clinical trials thus far have been shown to have manageable toxicity profiles and have demonstrated cytostatic effects as single agents, extending progression-free survival without producing a clinical or radiographic response. Trials are currently underway to strengthen the efficacy of treatment by combining FAK inhibitors with cytotoxic chemotherapy, targeted therapy, or immunotherapy. In the future, prognostic markers must be identified to carefully select patients who could benefit from FAK inhibitor treatment alone or in combination strategies.
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http://dx.doi.org/10.1080/13543784.2020.1740680DOI Listing
April 2020

Stromal-epithelial interactions in prostate cancer: Overexpression of PAGE4 in stromal cells inhibits the invasive ability of epithelial cells.

J Cell Biochem 2020 11 31;121(11):4406-4418. Epub 2020 Jan 31.

Department of Urology, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, Shenyang, Liaoning, China.

It is now widely recognized that carcinoma-associated fibroblasts which are believed to be myofibroblasts, promote the transformation of prostate epithelial cells to cancer cells, enhance their proliferation and invasiveness, and induce the acquisition of resistance to cancer therapy and immune evasiveness. Prostate-associated gene 4 (PAGE4) is an intrinsically disordered protein that is remarkably prostate-specific. PAGE4 is also a stress-response protein that functions as a transcriptional regulator and is upregulated in early-stage prostate cancer (PCa) and its precursor lesions. However, PAGE4 is downregulated in high-grade PCa and metastatic disease. Here, we show that PAGE4 is highly expressed in the stromal cells surrounding the cancer-adjacent "normal" glands and low-grade PCa lesions but not in lesions proximal to high-grade PCa. Overexpression of PAGE4 in a stromal cell line inhibits the migration and invasion of PCa epithelial cells in multiple coculture systems. PAGE4 overexpression also inhibits the downregulation of E-cadherin in PCa epithelial cells when cocultured with stromal cells. Furthermore, signaling via tumor necrosis factor-α and transforming growth factor-β pathways is decreased in the stromal cells overexpressing PAGE4 suggesting that PAGE4 appears to play a protective role against disease progression by perturbing interactions between epithelial cells and stromal cells in PCa. Taken together, these findings support previous observations that upregulation of PAGE4 in PCa correlates with a better prognosis and highlight PAGE4 as a novel therapeutic target for early-stage "low-risk" disease.
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http://dx.doi.org/10.1002/jcb.29664DOI Listing
November 2020

Presence and structure-activity relationship of intrinsically disordered regions across mucins.

FASEB J 2020 02 5;34(2):1939-1957. Epub 2020 Jan 5.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.

Many members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to tumor invasion, metastasis, and immune evasion. The large size and extensive glycosylation present challenges to study the mucin structure using traditional methods, including crystallography. We offer the hypothesis that the functional versatility of mucins may be attributed to the presence of intrinsically disordered regions (IDRs) that provide dynamism and flexibility and that the IDRs offer potential therapeutic targets. Herein, we examined the links between the mucin structure and function based on IDRs, posttranslational modifications (PTMs), and potential impact on their interactome. Using sequence-based bioinformatics tools, we observed that mucins are predicted to be moderately (20%-40%) to highly (>40%) disordered and many conserved mucin domains could be disordered. Phosphorylation sites overlap with IDRs throughout the mucin sequences. Additionally, the majority of predicted O- and N- glycosylation sites in the tandem repeat regions occur within IDRs and these IDRs contain a large number of functional motifs, that is, molecular recognition features (MoRFs), which directly influence protein-protein interactions (PPIs). This investigation provides a novel perspective and offers an insight into the complexity and dynamic nature of mucins.
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http://dx.doi.org/10.1096/fj.201901898RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018569PMC
February 2020

Phenotypic Switching of Naïve T Cells to Immune-Suppressive Treg-Like Cells by Mutant KRAS.

J Clin Med 2019 Oct 18;8(10). Epub 2019 Oct 18.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

Oncogenic (mutant) Ras protein Kirsten rat sarcoma viral oncogene homolog (KRAS) promotes uncontrolled proliferation, altered metabolism, and loss of genome integrity in a cell-intrinsic manner. Here, we demonstrate that CD4 T cells when incubated with tumor-derived exosomes from mutant (MT) KRAS non-small-cell lung cancer (NSCLC) cells, patient sera, or a mouse xenograft model, induce phenotypic conversion to FOXP3 Treg-like cells that are immune-suppressive. Furthermore, transfecting T cells with MT KRAS cDNA alone induced phenotypic switching and mathematical modeling supported this conclusion. Single-cell sequencing identified the interferon pathway as the mechanism underlying the phenotypic switch. These observations highlight a novel cytokine-independent, cell-extrinsic role for KRAS in T cell phenotypic switching. Thus, targeting this new class of Tregs represents a unique therapeutic approach for NSCLC. Since KRAS is the most frequently mutated oncogene in a wide variety of cancers, the findings of this investigation are likely to be of broad interest and have a large scientific impact.
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http://dx.doi.org/10.3390/jcm8101726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832522PMC
October 2019

Monitoring and Determining Mitochondrial Network Parameters in Live Lung Cancer Cells.

J Clin Med 2019 Oct 18;8(10). Epub 2019 Oct 18.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA.

Mitochondria are dynamic organelles that constantly fuse and divide, forming dynamic tubular networks. Abnormalities in mitochondrial dynamics and morphology are linked to diverse pathological states, including cancer. Thus, alterations in mitochondrial parameters could indicate early events of disease manifestation or progression. However, finding reliable and quantitative tools for monitoring mitochondria and determining the network parameters, particularly in live cells, has proven challenging. Here, we present a 2D confocal imaging-based approach that combines automatic mitochondrial morphology and dynamics analysis with fractal analysis in live small cell lung cancer (SCLC) cells. We chose SCLC cells as a test case since they typically have very little cytoplasm, but an abundance of smaller mitochondria compared to many of the commonly used cell types. The 2D confocal images provide a robust approach to quantitatively measure mitochondrial dynamics and morphology in live cells. Furthermore, we performed 3D reconstruction of electron microscopic images and show that the 3D reconstruction of the electron microscopic images complements this approach to yield better resolution. The data also suggest that the parameters of mitochondrial dynamics and fractal dimensions are sensitive indicators of cellular response to subtle perturbations, and hence, may serve as potential markers of drug response in lung cancer.
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http://dx.doi.org/10.3390/jcm8101723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832496PMC
October 2019

Intrinsically disordered proteins and phenotypic switching: Implications in cancer.

Prog Mol Biol Transl Sci 2019 11;166:63-84. Epub 2019 Apr 11.

Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States. Electronic address:

It is now well established that intrinsically disordered proteins (IDPs) that constitute a large part of the proteome across the three kingdoms, play critical roles in several biological processes including phenotypic switching. However, dysregulated expression of IDPs that engage in promiscuous interactions can lead to pathological states. In this chapter, using cancer as a paradigm, we discuss how IDP conformational dynamics and the resultant conformational noise can modulate phenotypic switching. Thus, contrary to the prevailing wisdom that phenotypic switching is highly deterministic (has a genetic underpinning) in cancer, emerging evidence suggests that non-genetic mechanisms, at least in part due to the conformational noise, may also be a confounding factor in phenotypic switching.
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http://dx.doi.org/10.1016/bs.pmbts.2019.03.013DOI Listing
April 2020

EPHA2 mutations with oncogenic characteristics in squamous cell lung cancer and malignant pleural mesothelioma.

Oncogenesis 2019 Sep 4;8(9):49. Epub 2019 Sep 4.

Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.

Squamous cell carcinoma (SCC) and malignant pleural mesothelioma (MPM) are thoracic malignancies with very poor prognosis and limited treatment options. It is an established fact that most of the solid tumors have overexpression of EPHA2 receptor tyrosine kinase. EPHA2 is known to exhibit opposing roles towards cancer progression. It functions in inhibiting cancer survival and migration via a ligand and tyrosine kinase dependent signaling (Y772). Whereas it is known to promote tumor progression and cell migration through a ligand-independent signaling (S897). We analyzed the expression profile and mutational status of the ephrin receptor A2 (EPHA2) in SCC and MPM cell lines and primary patient specimens. The EPHA2 receptor was found to be either overexpressed, mutated or amplified in SCC and MPM. In particular, the EPHA2 mutants A859D and T647M were interesting to explore, A859D Y772 dead mutant exhibited lower levels of phosphorylation at Y772 compared to T647M mutant. Molecular Dynamics simulations studies suggested that differential changes in conformation might form the structural basis for differences in the level of EPHA2 activation. Consequently, A859D mutant cells exhibited increased proliferation as well as cell migration compared to controls and T647M mutant. Kinomics analysis demonstrated that the STAT3 and PDGF pathways were upregulated whereas signaling through CBL was suppressed. Considered together, the present work has uncovered the oncogenic characteristics of EPHA2 mutations in SSC and MPM reinstating the dynamics of different roles of EPHA2 in cancer. This study also suggests that a combination of doxazosin and other EPHA2 inhibitors directed to inhibit the pertinent signaling components may be a novel therapeutic strategy for MPM and Non-small cell lung cancer patients who have either EPHA2 or CBL alterations.
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http://dx.doi.org/10.1038/s41389-019-0159-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726628PMC
September 2019

The Mitochondrion as an Emerging Therapeutic Target in Cancer.

Trends Mol Med 2020 01 18;26(1):119-134. Epub 2019 Jul 18.

Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, CA, USA. Electronic address:

Mitochondria have emerged as important pharmacological targets because of their key role in cellular proliferation and death. In tumor tissues, mitochondria can switch metabolic phenotypes to meet the challenges of high energy demand and macromolecular synthesis. Furthermore, mitochondria can engage in crosstalk with the tumor microenvironment, and signals from cancer-associated fibroblasts can impinge on mitochondria. Cancer cells can also acquire a hybrid phenotype in which both glycolysis and oxidative phosphorylation (OXPHOS) can be utilized. This hybrid phenotype can facilitate metabolic plasticity of cancer cells more specifically in metastasis and therapy-resistance. In light of the metabolic heterogeneity and plasticity of cancer cells that had until recently remained unappreciated, strategies targeting cancer metabolic dependency appear to be promising in the development of novel and effective cancer therapeutics.
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http://dx.doi.org/10.1016/j.molmed.2019.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938552PMC
January 2020

Small Cell Lung Cancer Therapeutic Responses Through Fractal Measurements: From Radiology to Mitochondrial Biology.

J Clin Med 2019 Jul 16;8(7). Epub 2019 Jul 16.

City of Hope, Dept. of Medical Oncology and Therapeutics Research, Duarte, CA 91010, USA.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine disease with an overall 5 year survival rate of ~7%. Although patients tend to respond initially to therapy, therapy-resistant disease inevitably emerges. Unfortunately, there are no validated biomarkers for early-stage SCLC to aid in early detection. Here, we used readouts of lesion image characteristics and cancer morphology that were based on fractal geometry, namely fractal dimension (FD) and lacunarity (LC), as novel biomarkers for SCLC. Scanned tumors of patients before treatment had a high FD and a low LC compared to post treatment, and this effect was reversed after treatment, suggesting that these measurements reflect the initial conditions of the tumor, its growth rate, and the condition of the lung. Fractal analysis of mitochondrial morphology showed that cisplatin-treated cells showed a discernibly decreased LC and an increased FD, as compared with control. However, treatment with mdivi-1, the small molecule that attenuates mitochondrial division, was associated with an increase in FD as compared with control. These data correlated well with the altered metabolic functions of the mitochondria in the diseased state, suggesting that morphological changes in the mitochondria predicate the tumor's future ability for mitogenesis and motogenesis, which was also observed on the CT scan images. Taken together, FD and LC present ideal tools to differentiate normal tissue from malignant SCLC tissue as a potential diagnostic biomarker for SCLC.
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http://dx.doi.org/10.3390/jcm8071038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679065PMC
July 2019

Intrinsically Disordered Proteins in Chronic Diseases.

Biomolecules 2019 04 11;9(4). Epub 2019 Apr 11.

Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.

t is now increasingly evident that a large fraction of the human proteome comprises proteins that, under physiological conditions, lack fixed, ordered 3D structures as a whole or have segments that are not likely to form a defined 3D structure [...].
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http://dx.doi.org/10.3390/biom9040147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523076PMC
April 2019