Health & Medical Cancer & Oncology

Cancer Stem Cells: Responsible for Treatment Failure?

Cancer Stem Cells: Responsible for Treatment Failure?

Self-renewal


As CSCs are endowed with the ability to self-renew, a wave of preclinical investigations has tried to assess the therapeutic relevance of inhibiting developmental pathways (Hedgehog, Notch, TGF-β, Wnt and, more recently, Hippo) that regulate this process.

In clinical experiences, the Smoothened inhibitor GDC-0449 was effective in treating patients with basal cell carcinoma and medulloblastoma, tumors that are characterized by the constitutive activation of the signal due to mutational events in key pathway effectors, whereas antitumor efficacy against tumors with wild-type pathway components was not observed. Nevertheless, Hedgehog activation has been documented in a variety of CSC types, spanning from adenocarcinoma of the pancreas and colon cancer to breast cancer, chronic myeloid leukemia and multiple myeloma. In these tumors, pathway inhibition was associated with anti-CSC activity. In brain tumors, it has been demonstrated that pathway inhibition synergizes with temozolomide and with the EGFR tyrosine kinase inhibitor erlotinib. More recently, an efficient depletion of docetaxel-resistant prostate cancer cells – a cellular subset displaying potent tumor-initiating abilities – was achieved by combining Hedgehog and Notch inhibition. Moreover, the combined use of a stroma-targeting Hedgehog pathway inhibitor with a pharmacological inhibitor of the Nodal/Activin receptor Alk4/7 and gemcitabine suppressed the growth of pancreatic cancer patient-derived xenografts. The role of the TGF-β pathway in determining therapeutic resistance is further highlighted in triple-negative breast cancer, in which the TGF-β type I receptor kinase inhibitor LY2157299 reduced the chemotherapy-resistant CSC population in vivo.

Breast cancer represents a benchmark for exploring the efficacy of Notch neutralization in CSCs. Notch inhibition through siRNA or γ-secretase inhibitors impaired mammosphere formation and determined HER2 downregulation in tumor-initiating HER2-overexpressing cells. Recently, in a co-clinical trial designed to determine the maximum tolerated dose of the γ-secretase inhibitor MK-0752 administered sequentially with docetaxel in patients with advanced breast cancer, inhibition of Notch cleavage potentiated chemotherapy efficacy in patient-derived xenografts and reduced mammosphere-forming efficiency in patients who underwent serial biopsies. Beyond breast cancer, Notch inhibition impaired the tumor-forming ability of brain CSCs. Interestingly, it has been reported that the activation of Notch in brain CSCs is driven by ligands produced by endothelial cells, thus providing the biological background for cotargeting CSCs and their niches. Anti-DLL4 antibodies represent an alternative, and more specific, pharmacological strategy for Notch targeting. In colorectal cancer, this approach combined with irinotecan reduced the frequency of KRAS-mutant colon CSCs. However, it is worth considering that potential safety concerns emerged with DLL4 blockade, as vascular tumors and liver histopathological alterations were detected in DLL4-treated mice. Inhibition of the Notch pathway was associated with preliminary evidence of antitumor activity in an early clinical trial.

The role of Wnt and Hippo in controlling CSC fate is mostly confined to colon and breast cancers, respectively. Myofibroblast-secreted factors activated β-catenin-dependent transcription in colon cancer cells, restoring the stem-like state in more differentiated tumor cells, whereas TAZ, a key component of the Hippo cascade, was associated with tumor initiation ability in breast cancer. Importantly, we demonstrated that TAZ controls the metastatic capacity of breast CSCs and confers them resistance to chemotherapy. However, so far, no pharmacological strategies aimed at antagonizing these pathways have entered clinical trials.

SHARE
RELATED POSTS on "Health & Medical"
Greed Is Good? Cigars and Throat Cancer
Greed Is Good? Cigars and Throat Cancer
Top 7 Breast Cancer Sites
Top 7 Breast Cancer Sites
Newer Breast Cancer Drugs Aid Survival
Newer Breast Cancer Drugs Aid Survival
Mammograms Spot Cancers That May Not Be Dangerous
Mammograms Spot Cancers That May Not Be Dangerous
Aging, Frailty, and Chemotherapy
Aging, Frailty, and Chemotherapy
Pediatric Supportive Care (PDQ®): Supportive care - Patient Information [NCI]-Overview
Pediatric Supportive Care (PDQ®): Supportive care - Patient Information [NCI]-Overview
Information About Breast Cancer Treatment
Information About Breast Cancer Treatment
Many Consumers Don't Understand Sunscreen Labels, Study Finds
Many Consumers Don't Understand Sunscreen Labels, Study Finds
pictures of skin cancer
pictures of skin cancer
CML Treatment and Clinical Trials
CML Treatment and Clinical Trials
How to Diagnose Malignant Melanoma
How to Diagnose Malignant Melanoma
Management of Castration-Resistant Prostate Cancer
Management of Castration-Resistant Prostate Cancer
Symptoms of Skin Cancer
Symptoms of Skin Cancer
Red Wine Antioxidant Fights Cancer
Red Wine Antioxidant Fights Cancer
How Effectively Combination Chemotherapy Works?
How Effectively Combination Chemotherapy Works?
Colon Cancer is Preventable - Don't Die From This Disease!
Colon Cancer is Preventable - Don't Die From This Disease!
Colon Health Check - Self Test For Early Colon Cancer Detection
Colon Health Check - Self Test For Early Colon Cancer Detection
Brachytherapy
Brachytherapy
Brain Cancer and Gliomas
Brain Cancer and Gliomas
Sheryl Crow's Battle with Breast Cancer
Sheryl Crow's Battle with Breast Cancer

Leave Your Reply

*