HDAC Inhibition in Cancer Therapy: An Increasingly Intriguing Tale of Chemistry, Biology and Clinical Benefit

2007 ◽  
pp. 293-331 ◽  
Author(s):  
P. ten Holte ◽  
K. Van Emelen ◽  
M. Janicot ◽  
P. C. Fong ◽  
J. S. de Bono ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Clinical Benefit ◽  
Hdac Inhibition

Clinical and translational investigation of pan-HDAC inhibition in advanced urothelial carcinoma (UC).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 379-379 ◽  
Author(s):  
Sumati Gupta ◽  
Daniel Joseph Albertson ◽  
Timothy Parnell ◽  
Brian Dalley ◽  
John O Shea ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Cell Lines ◽  
Cancer Cell ◽  
Clinical Benefit ◽  
Cancer Cell Lines ◽  
Differential Sensitivity ◽  
Bladder Cancer Cell ◽  
Hdac Inhibition ◽  
Translational Studies

379 Background: Pan-HDAC inhibitors were studied in two separate phase I pharmacokinetic solid tumor trials at Huntsman Cancer Institute. The objective of this study was to investigate the clinical efficacy of HDAC inhibition in those study subjects with UC and correlate response to molecular subtype of tumor with translational studies to validate clinical benefit. Methods: Patients with UC treated with a pan-HDAC inhibitor in two Phase I trials were included. RECIST 1.1 was used to categorize responses. Expression profiling and TCGA clustering were performed using archived tissue (obtainable for seven of the ten subjects). To elucidate the mechanisms of clinical benefit bladder cancer cell lines with varied mutational profiles and differential sensitivity to cisplatin were tested for sensitivity to panobinostat with characterization of phenotypic changes upon treatment. Results: Ten subjects with advanced UC received either belinostat or panobinostat. The best overall responses in the pooled data were: 1 complete response (CR), 1 partial response (PR), 6 stable disease (SD), 2 progressive disease (PD). The patient with CR had failed two prior lines of chemotherapy (including cisplatin), had a Cluster IV tumor and remains in CR for 3.5 years now. All tumors with SD belong to Cluster I. For those with SD, the progression free survival ranged from 6 to 7.5 months on treatment. One tumor with PR and one tumor with PD had characteristics partly consistent with Cluster III. Validating the broad spectrum of clinical activity of pan-HDAC inhibition, potent cytotoxicity with panobinostat was noted in bladder cancer cell lines with varied chromatin remodeling mutations. Panobinostat causes inhibition of colony formation, cell cycle arrest and proinflammatory cytokine release in these cells. Cisplatin-resistant HT1197 cells (with ARID1A mutation) are tenfold more sensitive. Conclusions: Pan-HDAC inhibition may be an effective treatment option in both luminal and basal subtypes of UC and in platinum-resistant setting. Translational studies suggest options for rational therapeutic combinations to enhance efficacy. HDAC inhibition may be particularly effective in UC with mutations affecting the SWI/SNF complex.

EXTH-76. DEVELOPING THE NOVEL COMBINATION THERAPY OPTIONS FOR CANCER THERAPY USING TUMOR TREATING FIELDS TOGETHER WITH THE CHEMO AGENTS TARGETING THE REPLICATION STRESS PATHWAY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi180-vi181
Author(s):  
Narasimha Kumar Karanam ◽  
Michael Story
Keyword(s):  
Dna Repair ◽  
Cancer Therapy ◽  
Clinical Benefit ◽  
Critical Role ◽  
Replication Stress ◽  
Cell Killing ◽  
Dna Breaks ◽  
Repair Capacity ◽  
Tumor Treating Fields ◽  
Chemotherapy Agents

Abstract Tumor Treating Fields (TTFields) as a component of cancer therapy has been shown to provide significant clinical benefit. The disruption of mitosis was identified as the first mechanism of action, however, a novel role for TTFields outside of mitosis where TTFields downregulates the Fanconi’s Anemia genes and proteins results in replication stress and reduced DNA repair capacity. Given these results we hypothesized that TTFields would increase the sensitivity of tumor cells to chemotherapy agents that increase replication stress. An analysis of agents that target replication stress in different ways was initiated. PARP1: Targeting PARP1 protects DNA breaks by recruiting DNA repair and checkpoint proteins to the sites of damage. Using the PARP1 inhibitor olaparib followed by radiation resulted in synergistic cell killing compared to radiation or olaparib alone or in combination. Etoposide: Etoposide forms a ternary complex with topoisomerase II and prevents re-ligation of DNA strands to elicit DNA strand breaks and replication stress. When combined with TTFields cell killing increased synergistically vs. etoposide alone. AZD6738: ATR is an essential kinase regulator of the replication checkpoint that plays a critical role in safeguarding genome integrity from replication stress. The advantage of combining TTFields with the ATR inhibitor-AZD6738 was tested for cell killing and the combination vs. AZD6738 was found to be synergistic. Irinotecan: Irinotecan traps topoisomerase I- DNA in a ternary cleavage complex and inhibits the initial cleavage reaction and re-ligation steps resulting in increased replication stress. Irinotecan and TTFields was tested and found to be highly effective at tumor cell killing. Collectively, our results suggest that it is likely of considerable clinical benefit to combine TTFields with chemotherapy agents that cause replication stress. This notion may explain the results of a number of clinical trials and suggests that there may be novel TTFields/replication stress-inducing chemotherapy agent combinations worth exploring.

Multifunctional metal–organic framework heterostructures for enhanced cancer therapy

2021 ◽  
Author(s):  
Jintong Liu ◽  
Jing Huang ◽  
Lei Zhang ◽  
Jianping Lei
Keyword(s):  
Cancer Therapy ◽  
General Principle ◽  
Biomedical Applications ◽  
Metal Organic Framework ◽  
Metal Organic ◽  
Functional Modulation ◽  
Organic Framework

We review the general principle of the design and functional modulation of nanoscaled MOF heterostructures, and biomedical applications in enhanced therapy.

918: Evaluation of the Clinical Benefit of Permixon and Tamsulosin in Severe BPH Patients – Permal Study Sub-Set Analysis

2004 ◽  
Vol 171 (4S) ◽  
pp. 243-244 ◽  
Author(s):  
Frans Debruyne ◽  
Peter Boyle ◽  
Remigio Vela-Navarrete ◽  
Fernando Calais Da Silva ◽  
Pierre Teillac ◽  
...  
Keyword(s):  
Clinical Benefit

Erythropoietin for HCV May Lack Clinical Benefit

2008 ◽  
Vol 41 (9) ◽  
pp. 52
Author(s):  
MICHELE G. SULLIVAN
Keyword(s):  
Clinical Benefit

Molecular profiling informs ovarian cancer therapy

2006 ◽  
Author(s):  
Heather Maisey
Keyword(s):  
Ovarian Cancer ◽  
Cancer Therapy ◽  
Molecular Profiling

Traditional and Enhanced Parent Training Show Similar Levels of Clinical Benefit in Single Mothers

2015 ◽  
Author(s):  
E. Rajwan ◽  
A. Chacko ◽  
B.T. Wymbs ◽  
F.A. Wymbs
Keyword(s):  
Parent Training ◽  
Single Mothers ◽  
Clinical Benefit

Cancer therapy targets rigid tissue

Nature ◽  
2017 ◽  
Vol 548 (7665) ◽  
pp. 9-9
Keyword(s):  
Cancer Therapy ◽  
Therapy Targets
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