Targeted Cancer Therapy (Closed)

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Therapy".

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Departments of Melanoma Medical Oncology and Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: computational cancer genomics; next generation sequencing; targeted therapy; immunotherapy; target discovery; drug repurposing; rare cancers
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Topical Collection Information

Dear Colleagues,

Targeted therapy is one of the major cancer treatment methods available today. The identification of tumor-specific drug targets allows precise targeting of cancer cells while minimizing damage to healthy tissues. Comprehensive genomic characterization of tumor types has helped to advance the development of novel therapies for precision oncology. However, the identification of novel druggable targets, relevant mechanisms, and effective combination therapies is needed. The development of resistance through intrinsic and acquired genomic alterations and signaling to targeted therapy, resulting in exceptional responses lasting for only a short duration, is still a major issue. Furthermore, the success of novel therapies may be hindered by adverse side effects. The objective of the current Topical Collection in Cancers is to publish original research papers and reviews from authors who are interested in addressing these challenges and provide new insights and novel treatment strategies for targeted cancer therapies.

Dr. Jason Roszik
Collection Editor

Manuscript Submission Information

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Keywords

  • targeted therapies
  • drug discovery
  • combination therapies
  • drug resistance mechanisms

Published Papers (3 papers)

2023

Jump to: 2022

21 pages, 2354 KiB  
Article
Comparative Effectiveness of First-Line Selpercatinib versus Standard Therapies in Patients with RET-Activated Cancers: An Exploratory Interpatient Analysis of LIBRETTO-001
by Filippo De Braud, Barbara Deschler-Baier, John C. Morris III, Francis Worden, Yimei Han, Urpo Kiiskinen, Min-Hua Jen, Scott S. Barker, Sylwia Szymczak and Adrienne M. Gilligan
Cancers 2024, 16(1), 140; https://doi.org/10.3390/cancers16010140 - 27 Dec 2023
Viewed by 1856
Abstract
Selpercatinib is indicated for locally advanced/metastatic RET-activated solid tumors after progression or following prior systemic therapies. Until the recently published data from LIBRETTO-431 and LIBRETTO-531, there were limited effectiveness data comparing selpercatinib with other first-line treatments in RET-activated non-small cell lung [...] Read more.
Selpercatinib is indicated for locally advanced/metastatic RET-activated solid tumors after progression or following prior systemic therapies. Until the recently published data from LIBRETTO-431 and LIBRETTO-531, there were limited effectiveness data comparing selpercatinib with other first-line treatments in RET-activated non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and thyroid cancer (TC). This study analyzed patient data from LIBRETTO-001 and compared the outcomes (time to treatment discontinuation {TTD}, time to next treatment or death {TTNT-D}, time to progression {TTP}, and the objective response rate {ORR}) of first-line selpercatinib (selpercatinib arm) use with the outcomes of first-line standard therapies in patients who then received selpercatinib in later lines of treatment (comparator arm). Overall, the first-line selpercatinib arm had a longer TTD, TTNT-D, and TTP versus the first-line comparator arm. The hazard ratios (HRs) for TTD were 0.29 (NSCLC), 0.15 (MTC), 0.08 (TC); for TTNT-D, the HRs were 0.48 (NSCLC), 0.11 (MTC), 0.09 (TC); and for TTP, the HRs were 0.54 (NSCLC), 0.15 (MTC), and 0.12 (TC). The ORR was higher for first-line selpercatinib versus the first-line comparator (NSCLC: 85.3% vs. 39.7%; MTC: 82.6% vs. 15.2%; and TC: 81.8% vs. 31.8%). First-line selpercatinib use is associated with improved outcomes compared to first-line comparator therapies for patients with advanced/metastatic RET-activated cancers. Full article
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2022

Jump to: 2023

19 pages, 2431 KiB  
Article
Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study)
by Hong-Shuai Li, Shou-Zheng Wang, Hai-Yan Xu, Xiang Yan, Jin-Yao Zhang, Si-Yu Lei, Teng Li, Xue-Zhi Hao, Tao Zhang, Guang-Jian Yang, Li-Qiang Zhou, Peng Liu, Yu-Ying Wang, Xing-Sheng Hu, Pu-Yuan Xing and Yan Wang
Cancers 2022, 14(21), 5307; https://doi.org/10.3390/cancers14215307 - 28 Oct 2022
Cited by 10 | Viewed by 2749
Abstract
(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no [...] Read more.
(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations. Full article
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26 pages, 1212 KiB  
Review
“FLipping” the Story: FLT3-Mutated Acute Myeloid Leukemia and the Evolving Role of FLT3 Inhibitors
by Tristan E. Knight, Holly Edwards, Soheil Meshinchi, Jeffrey W. Taub and Yubin Ge
Cancers 2022, 14(14), 3398; https://doi.org/10.3390/cancers14143398 - 13 Jul 2022
Cited by 12 | Viewed by 4194
Abstract
The treatment of many types of cancers, including acute myeloid leukemia (AML), has been revolutionized by the development of therapeutics targeted at crucial molecular drivers of oncogenesis. In contrast to broad, relatively indiscriminate conventional chemotherapy, these targeted agents precisely disrupt key pathways within [...] Read more.
The treatment of many types of cancers, including acute myeloid leukemia (AML), has been revolutionized by the development of therapeutics targeted at crucial molecular drivers of oncogenesis. In contrast to broad, relatively indiscriminate conventional chemotherapy, these targeted agents precisely disrupt key pathways within cancer cells. FMS-like tyrosine kinase 3 (FLT3)—encoding a critical regulator of hematopoiesis—is the most frequently mutated gene in patients with AML, and these mutations herald reduced survival and increased relapse in these patients. Approximately 30% of newly diagnosed AML carries an FLT3 mutation; of these, approximately three-quarters are internal tandem duplication (ITD) mutations, and the remainder are tyrosine kinase domain (TKD) mutations. In contrast to its usual, tightly controlled expression, FLT3-ITD mutants allow constitutive, “run-away” activation of a large number of key downstream pathways which promote cellular proliferation and survival. Targeted inhibition of FLT3 is, therefore, a promising therapeutic avenue. In April 2017, midostaurin became both the first FLT3 inhibitor and the first targeted therapy of any kind in AML to be approved by the US FDA. The use of FLT3 inhibitors has continued to grow as clinical trials continue to demonstrate the efficacy of this class of agents, with an expanding number available for use as both experimental standard-of-care usage. This review examines the biology of FLT3 and its downstream pathways, the mechanism of FLT3 inhibition, the development of the FLT3 inhibitors as a class and uses of the agents currently available clinically, and the mechanisms by which resistance to FLT3 inhibition may both develop and be overcome. Full article
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