Heart Failure With Targeted Cancer Therapies

Oncology has seen growing use of newly developed targeted therapies. Although this has resulted in dramatic improvements in progression-free and overall survival, challenges in the management of toxicities related to longer-term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and noncancer cells, overlap in signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities are of important concern. In this review, we highlight several targeted therapies commonly used across a variety of cancer types, including HER2 (human epidermal growth factor receptor 2)+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK (mitogen-activated protein kinase kinase)/BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors. We present the oncological indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity, and potential mechanistic rationale for specific cardioprotective strategies.

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The Molecular and Microenvironmental Landscape of Glioblastomas: Implications for the Novel Treatment Choices

Frontiers in Neuroscience ◽

10.3389/fnins.2020.603647 ◽

2020 ◽

Vol 14 ◽

Author(s):

Federica Di Cintio ◽

Michele Dal Bo ◽

Lorena Baboci ◽

Elena De Mattia ◽

Maurizio Polano ◽

...

Keyword(s):

Targeted Therapies ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Small Cell Lung Carcinoma ◽

Alkylating Agents ◽

Tumor Infiltrating Lymphocytes ◽

Cell Types ◽

Molecular Signature ◽

Central Nervous System Tumor ◽

Cell Lung Carcinoma

Glioblastoma (GBM) is the most frequent and aggressive primary central nervous system tumor. Surgery followed by radiotherapy and chemotherapy with alkylating agents constitutes standard first-line treatment of GBM. Complete resection of the GBM tumors is generally not possible given its high invasive features. Although this combination therapy can prolong survival, the prognosis is still poor due to several factors including chemoresistance. In recent years, a comprehensive characterization of the GBM-associated molecular signature has been performed. This has allowed the possibility to introduce a more personalized therapeutic approach for GBM, in which novel targeted therapies, including those employing tyrosine kinase inhibitors (TKIs), could be employed. The GBM tumor microenvironment (TME) exerts a key role in GBM tumor progression, in particular by providing an immunosuppressive state with low numbers of tumor-infiltrating lymphocytes (TILs) and other immune effector cell types that contributes to tumor proliferation and growth. The use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers as well as promising results have been shown for the use of these antibodies in untreated brain metastases from melanoma and from non-small cell lung carcinoma (NSCLC). Consequently, the use of PD-1/PD-L1 inhibitors has also been proposed in several clinical trials for the treatment of GBM. In the present review, we will outline the main GBM molecular and TME aspects providing also the grounds for novel targeted therapies and immunotherapies using ICIs for GBM.

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Cardiovascular Health during and after Cancer Therapy

Cancers ◽

10.3390/cancers12123737 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3737

Author(s):

Kathryn J. Ruddy ◽

Shruti R. Patel ◽

Alexandra S. Higgins ◽

Saro H. Armenian ◽

Joerg Herrmann

Keyword(s):

Cancer Therapy ◽

Cardiovascular Health ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Proteasome Inhibitors ◽

Growth Factor Receptor ◽

Marrow Transplant ◽

T Cell Therapy ◽

Cardiovascular Side Effects ◽

After Cancer

Certain cancer treatments have been linked to specific cardiovascular toxicities, including (but not limited to) cardiomyopathy, atrial fibrillation, arterial hypertension, and myocarditis. Radiation, anthracyclines, human epidermal growth factor receptor 2 (Her2)-directed therapies, fluoropyrimidines, platinums, tyrosine kinase inhibitors and proteasome inhibitors, immune checkpoint inhibitors, and chimeric antigen-presenting (CAR)-T cell therapy can all cause cardiovascular side effects. Management of cardiovascular dysfunction that occurs during cancer therapy often requires temporary or permanent cessation of the risk-potentiating anti-neoplastic drug as well as optimization of medical management from a cardiovascular standpoint. Stem cell or bone marrow transplant recipients face unique cardiovascular challenges, as do patients at extremes of age.

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DRES-13. DUAL KINASE INHIBITION TO COMBAT EGFR-INHIBITOR RESISTANCE IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.300 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi74-vi74

Author(s):

Erin Smithberger ◽

Abigail Shelton ◽

Madison Butler ◽

Alex Flores ◽

Ryan Bash ◽

...

Keyword(s):

Kinase Inhibitors ◽

Alternative Pathway ◽

Growth Factor Receptor ◽

Cell Types ◽

Genetically Engineered ◽

Differentially Expressed ◽

Egfr Inhibitor ◽

Tumor Resistance ◽

Pten Deletion ◽

In Cells

Abstract Glioblastoma (GBM) is an aggressive primary brain tumor with a poor survival rate. One of the most common molecular alterations seen in GBM is amplification and/or mutation of the Epidermal Growth Factor Receptor (EGFR), which has made it an attractive therapeutic target. However, several EGFR tyrosine kinase inhibitors have been tested clinically in GBM with minimal success. One reason for this lack of efficacy could be due to acute, adaptive resistance via alternative pathway activation. To investigate this mechanism of tumor resistance, we used RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the transcriptomes and kinomes of genetically engineered murine astrocytes with common GBM genotypes. We have previously shown that 38% of the expressed kinome varied among a panel of diverse nGEM astrocytes harboring Cdkn2a deletion (C) plus Pten deletion (CP), wild-type human EGFR (CE) or EGFRvIII (CEv3) overexpression or both EGFRvIII overexpression and Pten deletion (CEv3P). Although CE have a similar transcriptional profile to C cells at baseline, when treated with the EGFR inhibitor afatinib, CE respond more similarly to CEv3 cells. When cells containing endogenous murine EGFR (C and CP) are treated with afatinib, fewer than 0.5% of kinases showed differential expression. In cells with EGFR overexpression alone, more than 6% of kinases were differentially expressed upon afatinib treatment, including Ntrk3, Fgfr2 and 3, Lyn, Bmx, Epha2 and 5, Fn3k, a kinase involved in fructosamine processing, and Nrbp2, a kinase involved in regulation of apoptosis. This effect was blunted in cells lacking Pten in addition to having EGFRvIII (CEv3P), resulting in less than 2% of kinases being differentially expressed. The only kinase upregulated in all three EGFR-overexpressing cell types was Coq8a, which is involved in electron transport and response to DNA damage. Given this overlap in response, Coq8a could be a potential dual treatment target for GBM.

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Patient-derived models of acquired resistance can identify effective drug combinations for cancer

Science ◽

10.1126/science.1254721 ◽

2014 ◽

Vol 346 (6216) ◽

pp. 1480-1486 ◽

Cited By ~ 418

Author(s):

Adam S. Crystal ◽

Alice T. Shaw ◽

Lecia V. Sequist ◽

Luc Friboulet ◽

Matthew J. Niederst ◽

...

Keyword(s):

Growth Factor ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Drug Combinations ◽

Effective Drug ◽

Cancer Therapies ◽

Lung Cancer Patients ◽

Anaplastic Lymphoma ◽

Culture Models

Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.

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KRASoncogene in lung cancer: focus on molecularly driven clinical trials

European Respiratory Review ◽

10.1183/16000617.0071-2015 ◽

2016 ◽

Vol 25 (139) ◽

pp. 71-76 ◽

Cited By ~ 31

Author(s):

Emmanuelle Kempf ◽

Benoît Rousseau ◽

Benjamin Besse ◽

Luis Paz-Ares

Keyword(s):

Kinase Inhibitors ◽

Mammalian Target Of Rapamycin ◽

Growth Factor Receptor ◽

Mitogen Activated Protein Kinase ◽

Phase Iii ◽

Phase Iii Trial ◽

Lung Cancers ◽

Molecular Abnormalities ◽

Mitogen Activated Protein ◽

Pathway Inhibition

KRASmutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically forKRAS-mutated NSCLC patients. Direct inhibition ofRASactivation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients’ clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and epidermal growth factor receptor proteins is currently being assessed in early-phase trials. The association with mammalian target of rapamycin pathway inhibition leads to non-manageable toxicity. Other strategies, such as inhibition of molecular heat-shock proteins 90 or focal adhesion kinase are currently assessed. Abemaciclib, a cyclin-dependent kinase 4/6 inhibitor, showed promising results in a phase I trial, with a 54% disease control rate. Results of an ongoing phase III trial are warranted. Immunotherapy might be the next relevant step inKRAS-mutated NSCLC management due to the high burden of associated mutations and neo-antigens.

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Evolving Treatment Paradigm in Metastatic Renal Cell Carcinoma

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_174469 ◽

2017 ◽

pp. 319-329

Author(s):

David M. Gill ◽

Neeraj Agarwal ◽

Ulka Vaishampayan

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Targeted Therapies ◽

Renal Cell ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Checkpoint Inhibitors ◽

Mtor Inhibitors ◽

Treatment Paradigm

The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel–Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA’s approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents.

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

International Journal of Molecular Sciences ◽

10.3390/ijms19082380 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2380 ◽

Cited By ~ 13

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.

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Mos in the Oocyte: How to Use MAPK Independently of Growth Factors and Transcription to Control Meiotic Divisions

Journal of Signal Transduction ◽

10.1155/2011/350412 ◽

2011 ◽

Vol 2011 ◽

pp. 1-15 ◽

Cited By ~ 21

Author(s):

Aude Dupré ◽

Olivier Haccard ◽

Catherine Jessus

Keyword(s):

Growth Factors ◽

Transcriptional Activation ◽

Biological Activities ◽

Growth Factor Receptor ◽

Cell Types ◽

Mitogen Activated Protein Kinase ◽

Specific Cell ◽

Cell Type ◽

Specific Cell Type ◽

Mitogen Activated Protein

In many cell types, the mitogen-activated protein kinase (MAPK) also named extracellular signal-regulated kinase (ERK) is activated in response to a variety of extracellular growth factor-receptor interactions and leads to the transcriptional activation of immediate early genes, hereby influencing a number of tissue-specific biological activities, as cell proliferation, survival and differentiation. In one specific cell type however, the female germ cell, MAPK does not follow this canonical scheme. In oocytes, MAPK is activated independently of growth factors and tyrosine kinase receptors, acts independently of transcriptional regulation, plays a crucial role in controlling meiotic divisions, and is under the control of a peculiar upstream regulator, the kinase Mos. Mos was originally identified as the transforming gene of Moloney murine sarcoma virus and its cellular homologue was the first proto-oncogene to be molecularly cloned. What could be the specific roles of Mos that render it necessary for meiosis? Which unique functions could explain the evolutionary cost to have selected one gene to only serve for few hours in one very specific cell type? This review discusses the original features of MAPK activation by Mos and the roles of this module in oocytes.

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Targeted Therapies in Triple-Negative Breast Cancer

Breast Care ◽

10.1159/000433622 ◽

2015 ◽

Vol 10 (3) ◽

pp. 159-166 ◽

Cited By ~ 33

Author(s):

Frederik Marmé ◽

Andreas Schneeweiss

Keyword(s):

Breast Cancer ◽

Growth Factor ◽

Triple Negative Breast Cancer ◽

Targeted Therapies ◽

Triple Negative ◽

Checkpoint Inhibitors ◽

Chemotherapy Resistance ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Receptor Subtype

Triple-negative breast cancer (TNBC) is a heterogeneous disease comprised of several biologically distinct subtypes. However, treatment is currently mainly relying on chemotherapy as there are no targeted therapies specifically approved for TNBC. Despite initial responses to chemotherapy, resistance frequently and rapidly develops and metastatic TNBC has a poor prognosis. New targeted approaches are, therefore, urgently needed. Currently, bevacizumab, a monoclonal anti-vascular endothelial growth factor (VEGF)-A antibody, is the only targeted agent with an approval for the therapy of metastatic breast cancer, but does not provide a specific benefit in the TNBC subtype. This review discusses the current clinical developments in targeted approaches for TNBC, including anti-angiogenic therapies, epidermal growth factor receptor (EGFR)-targeted therapies, poly(ADP-ribose) polymerase (PARP) inhibitors and platinum salts, as well as novel strategies using immune-checkpoint inhibitors, which have recently demonstrated first promising results. Strategies focusing on specific subtypes of TNBC like anti-androgenic therapies for the luminal androgen receptor subtype (LAR) and others are also discussed.

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