scholarly journals Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 659
Author(s):  
Hon Yan Kelvin Yip ◽  
Antonella Papa
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
De Novo ◽  
Myelogenous Leukemia ◽  
Cancer Drug ◽  
Cancer Therapies ◽  
Cancer Genes ◽  
Her2 Positive ◽  
Molecular Alterations ◽  
Positive Breast Cancer

Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.

scholarly journals Hormonal treatment combined with targeted therapies in endocrine-responsive and HER2-positive metastatic breast cancer

2019 ◽  
Vol 11 ◽  
pp. 175883591989410 ◽  
Author(s):  
Emilia Montagna ◽  
Marco Colleoni
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Signaling Pathways ◽  
Targeted Therapies ◽  
De Novo ◽  
Current Knowledge ◽  
Metastatic Breast ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Approximately 50% of HER2 positive breast cancer cases are also estrogen receptor (ER) positive. Data supports a role for close cross-talk between the ER and HER2 signaling pathways as an important contributor to the development of de novo or acquired resistance to hormone therapies. Therefore a strategy that simultaneously blocks both signaling pathways is a reasonable approach to prevent or overcome either endocrine or anti-HER2 therapy resistance. Moreover, preclinical data support the idea that PI3K inhibitors and CDK4/6 could be an attractive target that functions downstream of both ER and HER2 pathways. We conducted a literature review of the results of phase II and III studies testing targeted therapies in metastatic breast cancer with HER2-positive and hormonal-receptor-positive disease. The analyses included efficacy and toxicity data from earlier studies with a single anti-HER2 drug combined with hormonal therapy up to more recent studies testing new molecules targeting these signaling pathways. The aims of this review are to summarize current knowledge and to discuss research development including the possibility to spare chemotherapy in this subgroup of HER2-positive breast cancer patients.

scholarly journals Androgen receptor signaling pathways as a target for breast cancer treatment

2016 ◽  
Vol 23 (10) ◽  
pp. R485-R498 ◽  
Author(s):  
Elisabetta Pietri ◽  
Vincenza Conteduca ◽  
Daniele Andreis ◽  
Ilaria Massa ◽  
Elisabetta Melegari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Triple Negative ◽  
Pubertal Development ◽  
Her2 Positive ◽  
Age Related ◽  
Clinical Scenarios ◽  
Er Positive ◽  
Positive Breast Cancer

The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

scholarly journals Evidence-Based Network Approach to Recommending Targeted Cancer Therapies

2020 ◽  
pp. 71-88 ◽  
Author(s):  
Jayaram Kancherla ◽  
Shruti Rao ◽  
Krithika Bhuvaneshwar ◽  
Rebecca B. Riggins ◽  
Robert A. Beckman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Evidence Based ◽  
Cancer Type ◽  
Cancer Therapies ◽  
Network Approach ◽  
Pathway Information ◽  
Molecular Alterations ◽  
Er Positive ◽  
Targeted Cancer Therapies ◽  
Positive Breast Cancer

PURPOSE In this work, we introduce CDGnet (Cancer-Drug-Gene Network), an evidence-based network approach for recommending targeted cancer therapies. CDGnet represents a user-friendly informatics tool that expands the range of targeted therapy options for patients with cancer who undergo molecular profiling by including the biologic context via pathway information. METHODS CDGnet considers biologic pathway information specifically by looking at targets or biomarkers downstream of oncogenes and is personalized for individual patients via user-inputted molecular alterations and cancer type. It integrates a number of different sources of knowledge: patient-specific inputs (molecular alterations and cancer type), US Food and Drug Administration–approved therapies and biomarkers (curated from DailyMed), pathways for specific cancer types (from Kyoto Encyclopedia of Genes and Genomes [KEGG]), gene-drug connections (from DrugBank), and oncogene information (from KEGG). We consider 4 different evidence-based categories for therapy recommendations. Our tool is delivered via an R/Shiny Web application. For the 2 categories that use pathway information, we include an interactive Sankey visualization built on top of d3.js that also provides links to PubChem. RESULTS We present a scenario for a patient who has estrogen receptor (ER)–positive breast cancer with FGFR1 amplification. Although many therapies exist for patients with ER-positive breast cancer, FGFR1 amplifications may confer resistance to such treatments. CDGnet provides therapy recommendations, including PIK3CA, MAPK, and RAF inhibitors, by considering targets or biomarkers downstream of FGFR1. CONCLUSION CDGnet provides results in a number of easily accessible and usable forms, separating targeted cancer therapies into categories in an evidence-based manner that incorporates biologic pathway information.

scholarly journals Breast Cancer Cells in Microgravity: New Aspects for Cancer Research

2020 ◽  
Vol 21 (19) ◽  
pp. 7345 ◽  
Author(s):  
Mohamed Zakaria Nassef ◽  
Daniela Melnik ◽  
Sascha Kopp ◽  
Jayashree Sahana ◽  
Manfred Infanger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Breast Cancer Cells ◽  
De Novo ◽  
Tumor Model ◽  
Cancer Drug ◽  
Cancer Therapies

Breast cancer is the leading cause of cancer death in females. The incidence has risen dramatically during recent decades. Dismissed as an “unsolved problem of the last century”, breast cancer still represents a health burden with no effective solution identified so far. Microgravity (µg) research might be an unusual method to combat the disease, but cancer biologists decided to harness the power of µg as an exceptional method to increase efficacy and precision of future breast cancer therapies. Numerous studies have indicated that µg has a great impact on cancer cells; by influencing proliferation, survival, and migration, it shifts breast cancer cells toward a less aggressive phenotype. In addition, through the de novo generation of tumor spheroids, µg research provides a reliable in vitro 3D tumor model for preclinical cancer drug development and to study various processes of cancer progression. In summary, µg has become an important tool in understanding and influencing breast cancer biology.

Relapsed and De Novo Metastatic HER2-positive Breast Cancer Treated With Trastuzumab: Tumor Genotypes and Clinical Measures Associated With Patient Outcome

2019 ◽  
Vol 19 (2) ◽  
pp. 113-125.e4 ◽  
Author(s):  
Vassiliki Kotoula ◽  
Kalliopi Tsakiri ◽  
Georgia-Angeliki Koliou ◽  
Georgios Lazaridis ◽  
Kyriaki Papadopoulou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Patient Outcome ◽  
De Novo ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Clinical Measures ◽  
Positive Breast Cancer

scholarly journals HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

2019 ◽  
Vol 11 ◽  
pp. 175883591983351 ◽  
Author(s):  
Sonia Pernas ◽  
Sara M. Tolaney
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Mtor Inhibitors ◽  
Therapy Resistance ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody–drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.

scholarly journals Breast Cancer Drug Resistance: Overcoming the Challenge by Capitalizing on MicroRNA and Tumor Microenvironment Interplay

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3691
Author(s):  
Giulia Cosentino ◽  
Ilaria Plantamura ◽  
Elda Tagliabue ◽  
Marilena V. Iorio ◽  
Alessandra Cataldo
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Triple Negative ◽  
Response To Therapy ◽  
Cancer Drug ◽  
Tumor Aggressiveness ◽  
Her2 Positive ◽  
Cancer Drug Resistance ◽  
Positive Breast Cancer

The clinical management of breast cancer reaches new frontiers every day. However, the number of drug resistant cases is still high, and, currently, this constitutes one of the major challenges that cancer research has to face. For instance, 50% of women affected with HER2 positive breast cancer presents or acquires resistance to trastuzumab. Moreover, for patients affected with triple negative breast cancer, standard chemotherapy is still the fist-line therapy, and often patients become resistant to treatments. Tumor microenvironment plays a crucial role in this context. Indeed, cancer-associated stromal cells deliver oncogenic cues to the tumor and vice versa to escape exogenous insults. It is well known that microRNAs are among the molecules exploited in this aberrant crosstalk. Indeed, microRNAs play a crucial function both in the induction of pro-tumoral traits in stromal cells and in the stroma-mediated fueling of tumor aggressiveness. Here, we summarize the most recent literature regarding the involvement of miRNAs in the crosstalk between tumor and stromal cells and their capability to modulate tumor microenvironment characteristics. All up-to-date findings suggest that microRNAs in the TME could serve both to reverse malignant phenotype of stromal cells, modulating response to therapy, and as predictive/prognostic biomarkers.

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