scholarly journals Targeted Therapies in Cancer: To Be or Not to Be, Selective

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1591
Author(s):  
Skye Montoya ◽  
Deborah Soong ◽  
Nina Nguyen ◽  
Maurizio Affer ◽  
Sailasya P. Munamarty ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Drug Exposure ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Treatment Options ◽  
Sequential Therapy ◽  
Oncogenic Signaling ◽  
Multikinase Inhibitor ◽  
Cancer Types ◽  
Goal Understanding

Development of targeted therapies in recent years revealed several nonchemotherapeutic options for patients. Chief among targeted therapies is small molecule kinase inhibitors targeting key oncogenic signaling proteins. Through competitive and noncompetitive inhibition of these kinases, and therefore the pathways they activate, cancers can be slowed or completely eradicated, leading to partial or complete remissions for many cancer types. Unfortunately, for many patients, resistance to targeted therapies, such as kinase inhibitors, ultimately develops and can necessitate multiple lines of treatment. Drug resistance can either be de novo or acquired after months or years of drug exposure. Since resistance can be due to several unique mechanisms, there is no one-size-fits-all solution to this problem. However, combinations that target complimentary pathways or potential escape mechanisms appear to be more effective than sequential therapy. Combinations of single kinase inhibitors or alternately multikinase inhibitor drugs could be used to achieve this goal. Understanding how to efficiently target cancer cells and overcome resistance to prior lines of therapy became imperative to the success of cancer treatment. Due to the complexity of cancer, effective treatment options in the future will likely require mixing and matching these approaches in different cancer types and different disease stages.

scholarly journals New Treatments for Renal Cell Carcinoma: Targeted Therapies

2009 ◽  
Vol 7 (6) ◽  
pp. 645-656 ◽  
Author(s):  
Philip J. Saylor ◽  
M. Dror Michaelson
Keyword(s):  
Renal Cell Carcinoma ◽  
Targeted Therapies ◽  
Mtor Inhibitor ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Treatment Options ◽  
Line Treatment ◽  
Second Line ◽  
Targeted Agents ◽  
First Line

Systemic treatment options for advanced renal cell carcinoma (RCC) have expanded considerably with the development of targeted therapies. Clear cell RCC commonly features mutation or inactivation of the von Hippel-Lindau gene and resultant overexpression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Since then, anti-VEGF receptor therapy with multitargeted kinase inhibitors also has shown substantial efficacy. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Other kinase inhibitors are in development. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival when used in second-line treatment. Non-clear cell and sarcomatoid RCC are both underrepresented in completed trials but are the subject of active research. Ongoing and planned studies will also evaluate the use of combinations of targeted agents, a strategy that is not advisable outside of clinical trials. Finally, postnephrectomy adjuvant treatment with targeted agents is not yet standard but is under investigation in phase III trials.

scholarly journals Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

2018 ◽  
Vol 19 (8) ◽  
pp. 2380 ◽  
Author(s):  
Michiel Remmerie ◽  
Veerle Janssens
Keyword(s):  
Clinical Trials ◽  
Endometrial Cancer ◽  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Type I ◽  
Type Ii

Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

Mechanisms of Resistance to Targeted Therapies in Acute Myeloid Leukemia and Chronic Myeloid Leukemia

2012 ◽  
pp. 685-689
Author(s):  
Catherine C. Smith ◽  
Neil P. Shah
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chronic Myeloid Leukemia ◽  
Targeted Therapies ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Oncogenic Signaling ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Clinical Resistance ◽  
Acute Myeloid

Overview: Small molecule kinase inhibitors of BCR-ABL in chronic myeloid leukemia (CML) and of FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in acute myeloid leukemia (AML) have been successful at achieving remissions in these diseases as monotherapy, but these leukemias do not initially respond in a subset of patients (primary resistance) and they progress in an additional group of patients after an initial response (secondary resistance). Resistance to these agents can be divided into mechanisms that allow reactivation kinase activity and those that bypass reliance on oncogenic signaling mediated by the target kinase. Elucidation of clinical resistance mechanisms to targeted therapies for patients can provide important insights into disease pathogenesis and signaling.

Growth factor receptor interplay and resistance in cancer

2006 ◽  
Vol 13 (Supplement_1) ◽  
pp. S45-S51 ◽  
Author(s):  
Helen E Jones ◽  
Julia M W Gee ◽  
Iain R Hutcheson ◽  
Janice M Knowlden ◽  
Denise Barrow ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
New Agents ◽  
Anti Cancer ◽  
Cancer Types ◽  
Epidermal Growth ◽  
High Level

Aberrant signalling through the epidermal growth factor receptor (EGFR) plays a major role in the progression and maintenance of the malignant phenotype and the receptor is therefore a rational anti-cancer target. A variety of approaches have been developed to specifically target the EGFR which include monoclonal antibodies and small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa). However, the recent clinical experience across a range of cancer types is revealing that despite the anti-EGFR agents demonstrating some anti-tumour activity, there is a high level of de novo and acquired resistance to such treatments and moreover, overexpression of the EGFR is clearly not the sole determinant of response to such therapies. Such adverse phenomena, which serve to limit the overall therapeutic impact of these new agents, implies the existence of a greater complexity involved in the regulation of EGFR signalling than was previously assumed. Indeed, evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR, and the IGF-1 receptor (IGF-1R) and the review will focus on the emerging concept of growth factor pathway switching between these two receptors as a means of influencing the effectiveness of anti-EGFR agents such as gefitinib.

Neurotrophic tyrosine kinase inhibitors: A review of implications for patients, clinicians and healthcare services

2020 ◽  
Vol 26 (8) ◽  
pp. 2015-2019
Author(s):  
Andrew Walker
Keyword(s):  
Targeted Therapies ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Healthcare Providers ◽  
Healthcare Services ◽  
New Approach ◽  
Regulatory Bodies ◽  
Targeted Agent ◽  
Tyrosine Receptor Kinase ◽  
To Receive

Neurotrophic tyrosine receptor kinase (NTRK) inhibitors represent the latest advancement as a treatment option in targeted therapies for malignant disease. NTRK gene fusions involving NTRK1, 2 or 3 are implicated as genetics drivers for a number of tumour types which arise within adult and paedatric patients. NTRK inhibitors (Larotrectinib and Entrectinib) are effective agents which have demonstrated clinical benefit in the treatment of NTRK fusion positive solid tumours. Larotrectinib represents the first targeted agent to receive approval from international authorisation and commissioning bodies for the treatment of a specific genetic expression indiscriminate of the site from which the tumour has arisen. As such NTRK inhibitors could pave the way for international healthcare bodies to adopt a similar approach for future targeted therapies thereby altering the manner in which healthcare providers and patients are able to access and utilise innovative, targeted treatment options in future. The potential implications of this new approach are likely to impact upon several aspects of the traditional authorisation and commissioning pathways with potential changes to the design of clinical trials, the review and approval process by regulatory bodies and immunohistopathology services.

scholarly journals The Oncogenic Signaling Pathways in BRAF-Mutant Melanoma Cells are Modulated by Naphthalene Diimide-Like G-Quadruplex Ligands

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1274 ◽  
Author(s):  
Recagni ◽  
Tassinari ◽  
Doria ◽  
Cimino-Reale ◽  
Zaffaroni ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Melanoma Cell ◽  
Targeted Therapies ◽  
Target Genes ◽  
Treatment Options ◽  
Melanoma Cells ◽  
Oncogenic Signaling ◽  
G Quadruplex ◽  
Oncogenic Signaling Pathways ◽  
Braf Mutant

Melanoma is the most aggressive and deadly type of skin cancer. Despite the advent of targeted therapies directed against specific oncogene mutations, melanoma remains a tumor that is very difficult to treat, and ultimately remains incurable. In the past two decades, stabilization of the non-canonical nucleic acid G-quadruplex structures within oncogene promoters has stood out as a promising approach to interfere with oncogenic signaling pathways in cancer cells, paving the way toward the development of G-quadruplex ligands as antitumor drugs. Here, we present the synthesis and screening of a library of differently functionalized core-extended naphthalene diimides for their activity against the BRAFV600E-mutant melanoma cell line. The most promising compound was able to stabilize G-quadruplexes that formed in the promoter regions of two target genes relevant to melanoma, KIT and BCL-2. This activity led to the suppression of protein expression and thus to interference with oncogenic signaling pathways involved in BRAF-mutant melanoma cell survival, apoptosis, and resistance to drugs. This G-quadruplex ligand thus represents a suitable candidate for the development of melanoma treatment options based on a new mechanism of action and could reveal particular significance in the context of resistance to targeted therapies of BRAF-mutant melanoma cells.

Emerging Strategies in Systemic Therapy for the Treatment of Melanoma

2018 ◽  
pp. 751-758 ◽  
Author(s):  
Paolo A. Ascierto ◽  
Keith Flaherty ◽  
Stephanie Goff
Keyword(s):  
Targeted Therapy ◽  
Targeted Therapies ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Adoptive Cell Transfer ◽  
Mek Inhibition

Recent years have seen major improvements in survival of patients with advanced melanoma with the advent of various novel systemic immunotherapies and targeted therapies. As our understanding of these agents and their various mechanisms of action improves, even more impressive outcomes are being achieved through use of various combination strategies, including the combining of different immunotherapies with one another as well as with other modalities. However, despite the improved outcomes that have been achieved in advanced melanoma, responses to treatment are heterogeneous and may not always be durable. Additional advances in therapy are required, and several emerging strategies are a focus of interest. These include the investigation of several new immunotherapy and/or targeted therapy combinations, such as checkpoint inhibitors (anti–PD-1/anti–CTLA-4) with other immunotherapies (e.g., indoleamine 2,3 dioxygenase [IDO] inhibitors, antilymphocyte activation 3 [anti–LAG-3], histone deacetylase [HDAC] inhibitors, Toll-like receptor 9 [TLR-9] agonists, antiglucocorticoid-induced tumor necrosis factor receptor [anti-GITR], pegylated interleukin-2 [IL-2]), combined targeted therapies (e.g., MEK and CDK4/6 coinhibition), and combined immunotherapy and targeted therapy (e.g., the triplet combination of BRAF/MEK inhibition with anti–PD-1s). The identification of novel therapeutic targets in the MAP kinase pathway also offers opportunities to improve outcomes by overcoming de novo and acquired resistance to BRAF/MEK inhibition (e.g., the development of ERK inhibitors). In addition, adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, may have a potential role in patients whose disease has progressed after immunotherapy. Taken together, these new approaches offer further potential to increase systemic treatment options and improve long-term outcomes for patients with advanced melanoma.

scholarly journals Therapeutic Options in Myelodysplastic Syndromes Following Hypomethylating Agent Failure

2020 ◽  
pp. 52-64
Author(s):  
Abigail Belasen ◽  
Shyamala C. Navada
Keyword(s):  
Myelodysplastic Syndromes ◽  
Targeted Therapies ◽  
Enzyme Inhibitor ◽  
Treatment Options ◽  
Gene Mutations ◽  
Therapeutic Options ◽  
Molecular Characteristics ◽  
Therapeutic Approaches ◽  
Multikinase Inhibitor ◽  
Idh Mutations

Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for the treatment of myelodysplastic syndromes (MDS). Although HMA have revolutionised the treatment of MDS, only approximately half of patients respond to these agents with variable duration of effect, known as primary and secondary HMA failure, respectively. Therapeutic options following HMA failure remain limited; however, growing understanding of the pathogenesis underlying MDS has resulted in the development of multiple targeted therapies showing varying degrees of success in clinical trials. Drugs that target molecular alterations (such as abnormal histone regulation, IDH mutations, and spliceosome gene mutations), abnormal signalling pathways (such as the multikinase inhibitor rigosertib), cellular apoptosis (such as the Bcl2 inhibitor venetoclax), and immune checkpoint inhibition are under development. Agents recently approved for use in higher-risk acute myeloid leukaemia, such as FLT3-inhibitors and CPX-351, are also being studied in MDS. Several more agents, including two first-in-class agents, a novel immune regulator targeting CD47, and pevonedistat, a NEDD8-activating enzyme inhibitor, are under investigation. In the absence of established therapeutic approaches following HMA failure, decisions in therapy should be based on the type of HMA resistance as well as the patient’s clinical and molecular characteristics. As targeted therapies continue to be developed, a comprehensive re-evaluation of the patient including the mutational profile at the time of HMA failure may reveal new treatment options. Here, emerging therapeutic approaches to HMA failure in MDS are reviewed.

scholarly journals CDK4/6 and MAPK—Crosstalk as Opportunity for Cancer Treatment

2020 ◽  
Vol 13 (12) ◽  
pp. 418
Author(s):  
Lisa Scheiblecker ◽  
Karoline Kollmann ◽  
Veronika Sexl
Keyword(s):  
Cell Cycle ◽  
Disease Resistance ◽  
Protein Kinases ◽  
Targeted Therapies ◽  
Alternative Treatment ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Resistance Mechanisms ◽  
Cancer Types ◽  
Cell Cycle Kinase

Despite the development of targeted therapies and novel inhibitors, cancer remains an undefeated disease. Resistance mechanisms arise quickly and alternative treatment options are urgently required, which may be partially met by drug combinations. Protein kinases as signaling switchboards are frequently deregulated in cancer and signify vulnerable nodes and potential therapeutic targets. We here focus on the cell cycle kinase CDK6 and on the MAPK pathway and on their interplay. We also provide an overview on clinical studies examining the effects of combinational treatments currently explored for several cancer types.

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