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Article ; Online: Inhibition of autophagy antagonizes breast cancer brain metastogenesis and augments the anticancer activity of lapatinib.

Nawrocki, Steffan T / Espitia, Claudia M / Espinoza, Maria Janina Carrera / Jones, Trace M / Gamble, Madison E / Sureshkumar, Sruthi / Chang, Mengyang / Wang, Wei / Carew, Jennifer S

Clinical and translational medicine

2024 Volume 14, Issue 4, Page(s) e1662

MeSH term(s)	Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Lapatinib/pharmacology ; Lapatinib/therapeutic use ; Humans ; Autophagy/drug effects ; Female ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Brain Neoplasms/drug therapy ; Brain Neoplasms/secondary ; Brain Neoplasms/pathology
Chemical Substances	Lapatinib (0VUA21238F) ; Antineoplastic Agents
Language	English
Publishing date	2024-04-24
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2697013-2
ISSN	2001-1326 ; 2001-1326
ISSN (online)	2001-1326
ISSN	2001-1326
DOI	10.1002/ctm2.1662
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Autophagy: New Insights into Its Roles in Cancer Progression and Drug Resistance.

Nawrocki, Steffan T / Wang, Wei / Carew, Jennifer S

Cancers

2020 Volume 12, Issue 10

Abstract: Autophagy is a mechanism of lysosomal proteolysis that is utilized to degrade damaged organelles, proteins, and other cellular components. Although key studies demonstrate that autophagy functions as a mechanism of tumor suppression via the degradation ... ...

Abstract	Autophagy is a mechanism of lysosomal proteolysis that is utilized to degrade damaged organelles, proteins, and other cellular components. Although key studies demonstrate that autophagy functions as a mechanism of tumor suppression via the degradation of defective pre-malignant cells, autophagy can also be used as a mechanism to break down cellular components under stress conditions to generate the required metabolic materials for cell survival. Autophagy has emerged as an important mediator of resistance to radiation, chemotherapy, and targeted agents. This series of articles highlight the role of autophagy in cancer progression and drug resistance and underscores the need for new and more effective agents that target this process.
Language	English
Publishing date	2020-10-16
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12103005
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Article ; Online: Selective Elimination of Senescent Cancer Cells by Galacto-Modified PROTACs.

Chang, Mengyang / Gao, Feng / Gnawali, Giri / Xu, Hang / Dong, Yue / Meng, Xiang / Li, Wenpan / Wang, Zhiren / Lopez, Byrdie / Carew, Jennifer S / Nawrocki, Steffan T / Lu, Jianqin / Zhang, Qing-Yu / Wang, Wei

Journal of medicinal chemistry

2024

Abstract: Although the selective and effective clearance of senescent cancer cells can improve cancer treatment, their development is confronted by many challenges. As part of efforts designed to overcome these problems, prodrugs, whose design is based on ... ...

Abstract	Although the selective and effective clearance of senescent cancer cells can improve cancer treatment, their development is confronted by many challenges. As part of efforts designed to overcome these problems, prodrugs, whose design is based on senescence-associated β-galactosidase (SA-β-gal), have been developed to selectively eliminate senescent cells. However, chemotherapies relying on targeted molecular inhibitors as senolytic drugs can induce drug resistance. In the current investigation, we devised a new strategy for selective degradation of target proteins in senescent cancer cells that utilizes a prodrug composed of the SA-β-gal substrate galactose (galacto) and the proteolysis-targeting chimeras (PROTACs) as senolytic agents. Prodrugs Gal-ARV-771 and Gal-MS99 were found to display senolytic indexes higher than those of ARV-771 and MS99. Significantly, results of
Language	English
Publishing date	2024-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.4c00152
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Article: Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer.

Jones, Trace M / Carew, Jennifer S / Bauman, Julie E / Nawrocki, Steffan T

Cancers

2021 Volume 13, Issue 13

Abstract: Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally ... ...

Abstract	Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally improved in the last three decades. New therapeutics that target novel pathways are desperately needed. NEDDylation is a key cellular process by which NEDD8 proteins are conjugated to substrate proteins in order to modulate their function. NEDDylation is closely tied to appropriate protein degradation, particularly proteins involved in cell cycle regulation, DNA damage repair, and cellular stress response. Components of the NEDDylation pathway are frequently overexpressed or hyperactivated in many cancer types including head and neck cancer, which contribute to disease progression and drug resistance. Therefore, targeting NEDDylation could have a major impact for malignancies with alterations in the pathway, and this has already been demonstrated in preclinical studies and clinical trials. Here, we will survey the mechanisms by which aberrant NEDDylation contributes to disease pathogenesis and discuss the potential clinical implications of inhibiting NEDDylation as a novel approach for the treatment of head and neck cancer.
Language	English
Publishing date	2021-06-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13133250
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Article: Therapeutic Targeting of Autophagy for Renal Cell Carcinoma Therapy.

Jones, Trace M / Carew, Jennifer S / Nawrocki, Steffan T

Cancers

2020 Volume 12, Issue 5

Abstract: Kidney cancer is the 7th most prevalent form of cancer in the United States with the vast majority of cases being classified as renal cell carcinoma (RCC). Multiple targeted therapies have been developed to treat RCC, but efficacy and resistance remain a ...

Abstract	Kidney cancer is the 7th most prevalent form of cancer in the United States with the vast majority of cases being classified as renal cell carcinoma (RCC). Multiple targeted therapies have been developed to treat RCC, but efficacy and resistance remain a challenge. In recent years, the modulation of autophagy has been shown to augment the cytotoxicity of approved RCC therapeutics and overcome drug resistance. Inhibition of autophagy blocks a key nutrient recycling process that cancer cells utilize for cell survival following periods of stress including chemotherapeutic treatment. Classic autophagy inhibitors such as chloroquine and hydroxychloroquine have been introduced into phase I/II clinical trials, while more experimental compounds are moving forward in preclinical development. Here we examine the current state and future directions of targeting autophagy to improve the efficacy of RCC therapeutics.
Language	English
Publishing date	2020-05-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12051185
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Article: Current Landscape of Immune Checkpoint Inhibitors for Metastatic Urothelial Carcinoma: Is There a Role for Additional T-Cell Blockade?

Ogbuji, Vanessa / Paster, Irasema C / Recio-Boiles, Alejandro / Carew, Jennifer S / Nawrocki, Steffan T / Chipollini, Juan

Cancers

2023 Volume 16, Issue 1

Abstract: ... on T-cells in urothelial carcinoma. The blockade of this immune checkpoint can lead to the reactivation ...

Abstract	Urothelial carcinoma (UC) is the most common form of bladder cancer (BC) and is the variant with the most immunogenic response. This makes urothelial carcinoma an ideal candidate for immunotherapy with immune checkpoint inhibitors. Key immune checkpoint proteins PD-1 and CTLA-4 are frequently expressed on T-cells in urothelial carcinoma. The blockade of this immune checkpoint can lead to the reactivation of lymphocytes and augment the anti-tumor immune response. The only immune checkpoint inhibitors that are FDA-approved for metastatic urothelial carcinoma target the programmed death-1 receptor and its ligand (PD-1/PD-L1) axis. However, the overall response rate and progression-free survival rates of these agents are limited in this patient population. Therefore, there is a need to find further immune-bolstering treatment combinations that may positively impact survival for patients with advanced UC. In this review, the current immune checkpoint inhibition treatment landscape is explored with an emphasis on combination therapy in the form of PD-1/PD-L1 with CTLA-4 blockade. The investigation of the current literature on immune checkpoint inhibition found that preclinical data show a decrease in tumor volumes and size when PD-1/PD-L1 is blocked, and similar results were observed with CTLA-4 blockade. However, there are limited investigations evaluating the combination of CTLA-4 and PD-1/PD-L1 blockade. We anticipate this review to provide a foundation for a deeper experimental investigation into combination immune checkpoint inhibition therapy in metastatic urothelial carcinoma.
Language	English
Publishing date	2023-12-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16010131
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Article ; Online: Targeting NEDDylation is a Novel Strategy to Attenuate Cisplatin-induced Nephrotoxicity.

Jones, Trace M / Espitia, Claudia M / Chipollini, Juan / Lee, Benjamin R / Wertheim, Jason A / Carew, Jennifer S / Nawrocki, Steffan T

Cancer research communications

2023 Volume 3, Issue 2, Page(s) 245–257

Abstract: Although cisplatin remains a backbone of standard-of-care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30%-40% of patients treated with cisplatin-based regimens are ... ...

Abstract	Although cisplatin remains a backbone of standard-of-care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30%-40% of patients treated with cisplatin-based regimens are forced to discontinue treatment after experiencing nephrotoxicity as a DLT. New approaches that simultaneously prevent renal toxicity while improving therapeutic response have the potential to make a major clinical impact for patients with multiple forms of cancer. Here, we report that pevonedistat (MLN4924), a first-in-class NEDDylation inhibitor, alleviates nephrotoxicity and synergistically enhances the efficacy of cisplatin in head and neck squamous cell carcinoma (HNSCC) models. We demonstrate that pevonedistat protects normal kidney cells from injury while enhancing the anticancer activity of cisplatin through a thioredoxin-interacting protein (TXNIP)-mediated mechanism. Cotreatment with pevonedistat and cisplatin yielded dramatic HNSCC tumor regression and long-term animal survival in 100% of treated mice. Importantly, the combination decreased nephrotoxicity induced by cisplatin monotherapy as evidenced by the blockade of kidney injury molecule-1 (KIM-1) and TXNIP expression, a reduction in collapsed glomeruli and necrotic cast formation, and inhibition of cisplatin-mediated animal weight loss. Inhibition of NEDDylation represents a novel strategy to prevent cisplatin-induced nephrotoxicity while simultaneously enhancing its anticancer activity through a redox-mediated mechanism. Significance: Cisplatin therapy is associated with significant nephrotoxicity, which limits its clinical use. Here we demonstrate that NEDDylation inhibition with pevonedistat is a novel approach to selectively prevent cisplatin-induced oxidative damage to the kidneys while simultaneously enhancing its anticancer efficacy. Clinical evaluation of the combination of pevonedistat and cisplatin is warranted.
MeSH term(s)	Mice ; Animals ; Cisplatin/adverse effects ; Squamous Cell Carcinoma of Head and Neck ; Apoptosis ; Drug-Related Side Effects and Adverse Reactions ; Head and Neck Neoplasms/drug therapy
Chemical Substances	Cisplatin (Q20Q21Q62J) ; pevonedistat (S3AZD8D215)
Language	English
Publishing date	2023-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-22-0340
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Article ; Online: Drain the lysosome: Development of the novel orally available autophagy inhibitor ROC-325.

Carew, Jennifer S / Nawrocki, Steffan T

Autophagy

2017 Volume 13, Issue 4, Page(s) 765–766

Abstract: Although macroautophagy/autophagy is a key contributor to malignant pathogenesis and therapeutic resistance, there are few FDA-approved agents that significantly affect this pathway. We used medicinal chemistry strategies to develop ROC-325, an orally ... ...

Abstract	Although macroautophagy/autophagy is a key contributor to malignant pathogenesis and therapeutic resistance, there are few FDA-approved agents that significantly affect this pathway. We used medicinal chemistry strategies to develop ROC-325, an orally available novel inhibitor of lysosomal-mediated autophagy. Detailed in vitro and in vivo studies in preclinical models of renal cell carcinoma demonstrated that ROC-325 triggered the hallmark features of lysosomal autophagy inhibition, was very well tolerated, and exhibited significant superiority with respect to autophagy inhibition and anticancer activity over hydroxychloroquine. Our findings support the clinical investigation of the safety and preliminary efficacy of ROC-325 in patients with autophagy-dependent malignancies and other disorders where aberrant autophagy contributes to disease pathogenesis.
MeSH term(s)	Administration, Oral ; Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Autophagy/drug effects ; Clinical Trials as Topic ; Humans ; Hydroxychloroquine/administration & dosage ; Hydroxychloroquine/chemistry ; Hydroxychloroquine/pharmacology ; Lysosomes/drug effects ; Lysosomes/metabolism ; Mice
Chemical Substances	Antineoplastic Agents ; Hydroxychloroquine (4QWG6N8QKH)
Language	English
Publishing date	2017-01-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2017.1280222
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Article ; Online: Targeting JAK/STAT Signaling Antagonizes Resistance to Oncolytic Reovirus Therapy Driven by Prior Infection with HTLV-1 in Models of T-Cell Lymphoma.

Islam, Shariful / Espitia, Claudia M / Persky, Daniel O / Carew, Jennifer S / Nawrocki, Steffan T

Viruses

2021 Volume 13, Issue 7

Abstract: Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people ... worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains ...

Abstract	Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains challenging and new treatment options are urgently needed. With the goal of developing a novel therapeutic approach for TCL, we investigated the activity of the clinical formulation of oncolytic reovirus (Reolysin, Pelareorep) in TCL models. Our studies revealed that HTLV-1-negative TCL cells were highly sensitive to Reolysin-induced cell death, but HTLV-1-positive TCL cells were resistant. Consistent with these data, reovirus displayed significant viral accumulation in HTLV-1-negative cells, but failed to efficiently replicate in HTLV-1-positive cells. Transcriptome analyses of HTLV-1-positive vs. negative cells revealed a significant increase in genes associated with retroviral infection including interleukin-13 and signal transducer and activator of transcription 5 (STAT5). To investigate the relationship between HTLV-1 status and sensitivity to Reolysin, we infected HTLV-1-negative cells with HTLV-1. The presence of HTLV-1 resulted in significantly decreased sensitivity to Reolysin. Treatment with the JAK inhibitor ruxolitinib suppressed STAT5 phosphorylation and expression of the key anti-viral response protein MX1 and enhanced the anti-TCL activity of Reolysin in both HTLV-1-positive and negative cells. Our data demonstrate that the inhibition of the JAK/STAT pathway can be used as a novel approach to antagonize the resistance of HTLV-1-positive cells to oncolytic virus therapy.
MeSH term(s)	Cell Line, Tumor ; Gene Expression Profiling ; Human T-lymphotropic virus 1 ; Humans ; Janus Kinases/antagonists & inhibitors ; Leukemia-Lymphoma, Adult T-Cell/therapy ; Leukemia-Lymphoma, Adult T-Cell/virology ; Nitriles/pharmacology ; Oncolytic Viruses/physiology ; Phosphorylation ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Reoviridae/physiology ; STAT5 Transcription Factor/antagonists & inhibitors ; Signal Transduction/drug effects
Chemical Substances	Nitriles ; Pyrazoles ; Pyrimidines ; STAT5 Transcription Factor ; reolysin ; ruxolitinib (82S8X8XX8H) ; Janus Kinases (EC 2.7.10.2)
Language	English
Publishing date	2021-07-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13071406
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Article ; Online: Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism.

Jones, Trace M / Espitia, Claudia M / Ooi, Aikseng / Bauman, Julie E / Carew, Jennifer S / Nawrocki, Steffan T

Cell death & disease

2022 Volume 13, Issue 4, Page(s) 350

Abstract: Patients with late-stage and human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) continue to have a very poor prognosis. The development of more effective novel therapies that improve overall survival and overcome drug ... ...

Abstract	Patients with late-stage and human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) continue to have a very poor prognosis. The development of more effective novel therapies that improve overall survival and overcome drug resistance is an urgent priority. Here we report that HNSCC tumors significantly overexpress NEDD8 and exhibit high sensitivity to the first-in-class NEDD8-activating enzyme (NAE) inhibitor pevonedistat. Additional studies established that disruption of NEDD8-mediated protein turnover with pevonedistat dramatically augmented cisplatin-induced DNA damage and apoptosis in HNSCC models. Further analysis revealed that the specific pevonedistat target CUL4A played an essential role in driving the synergy of the pevonedistat and cisplatin combination. Targeted inhibition of CUL4A resulted in significant downregulation in Damage Specific DNA binding protein 2 (DDB2), a DNA-damage recognition protein that promotes nucleotide excision repair and resistance to cisplatin. Silencing of CUL4A or DDB2 enhanced cisplatin-induced DNA damage and apoptosis in a manner similar to that of pevonedistat demonstrating that targeted inhibition of CUL4A may be a novel approach to augment cisplatin therapy. Administration of pevonedistat to mice bearing HNSCC tumors significantly decreased DDB2 expression in tumor cells, increased DNA damage and potently enhanced the activity of cisplatin to yield tumor regression and long-term survival of all animals. Our findings provide strong rationale for clinical investigation of CUL4A inhibition with pevonedistat as a novel strategy to augment the efficacy of cisplatin therapy for patients with HNSCC and identify loss of DDB2 as a key pharmacodynamic mediator controlling sensitivity to this regimen.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cisplatin/pharmacology ; Cullin Proteins/antagonists & inhibitors ; Cullin Proteins/genetics ; Cullin Proteins/metabolism ; DNA-Binding Proteins/antagonists & inhibitors ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Drug Synergism ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/genetics ; Head and Neck Neoplasms/metabolism ; Head and Neck Neoplasms/pathology ; Humans ; Mice ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; Squamous Cell Carcinoma of Head and Neck/genetics ; Squamous Cell Carcinoma of Head and Neck/metabolism ; Squamous Cell Carcinoma of Head and Neck/pathology
Chemical Substances	CUL4A protein, human ; Cullin Proteins ; DDB2 protein, human ; DNA-Binding Proteins ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2022-04-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-022-04798-6
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