Concise Review: Chronic Myeloid Leukemia: Stem Cell Niche and Response to Pharmacologic Treatment

Nowadays, more than 90% of patients affected by chronic myeloid leukemia (CML) survive with a good quality of life, thanks to the clinical efficacy of tyrosine kinase inhibitors (TKIs). Nevertheless, point mutations of the ABL1 pocket occurring during treatment may reduce binding of TKIs, being responsible of about 20% of cases of resistance among CML patients. In addition, the presence of leukemic stem cells (LSCs) represents the most important event in leukemia progression related to TKI resistance. LSCs express stem cell markers, including active efflux pumps and genetic and epigenetic alterations together with deregulated cell signaling pathways involved in self-renewal, such as Wnt/β-catenin, Notch, and Hedgehog. Moreover, the interaction with the bone marrow microenvironment, also known as hematopoietic niche, may influence the phenotype of surrounding cells, which evade mechanisms controlling cell proliferation and are less sensitive or frankly resistant to TKIs. This Review focuses on the role of LSCs and stem cell niche in relation to response to pharmacological treatments. A literature search from PubMed database was performed until April 30, 2017, and it has been analyzed according to keywords such as chronic myeloid leukemia, stem cell, leukemic stem cells, hematopoietic niche, tyrosine kinase inhibitors, and drug resistance. Stem Cells Translational Medicine 2018

Implications of KRAS mutations in acquired resistance to treatment in NSCLC

Rationale: KRAS is the most common and, simultaneously, the most ambiguous oncogene implicated in human cancer. Despite KRAS mutations were identified in Non Small Cell Lung Cancers (NSCLCs) more than 20 years ago, selective and specific inhibitors aimed at directly abrogating KRAS activity are not yet available. Nevertheless, many therapeutic approaches have been developed potentially useful to treat NSCLC patients mutated for KRAS and refractory to both standard chemotherapy and targeted therapies. The focus of this review will be to provide an overview of the network related to the intricate molecular KRAS pathways, stressing on preclinical and clinical studies that investigate the predictive value of KRAS mutations in NSCLC patients. Materials and Methods: A bibliographic search of the Medline database was conducted for articles published in English, with the keywords KRAS, KRAS mutations in non-small cell lung cancer, KRAS and tumorigenesis, KRAS and TKIs, KRAS and chemotherapy, KRAS and monoclonal antibody, KRAS and immunotherapy, KRAS and drugs, KRAS and drug resistance

Application of liquid biopsy to the monitoring of response to targeted therapy and immunotherapy in cancer patients.

In oncology to realize the so-called “precision medicine” the greatest challenge is to identify clinically significant variants that could be implemented in clinical practice “to provide the right dose of the right drug for the right patient at the right time”. Thus, the critical step is the characterization of the genetic profile of both cancer and individual, to decide which therapies a particular patient may benefit from, to discontinue the ineffective treatment, and to switch to another better therapy. Cell-free DNA (cfDNA) and exosomes-derived RNA can be extracted from the cell-free fraction of the blood, and provide a snapshot of the genetic profiles of primary and metastatic tumour sites, also called “liquid biopsy”. Although the detection of targetable mutations in cancer patients can be performed on tumour tissue, the monitoring of predictive biomarkers over the time to guide treatment selection is crucial, and liquid biopsy is a viable option for clinical practice. This work means greater reliance on the application of liquid biopsy in the diagnosis of resistance to targeted therapy and immunotherapy in Non-Small Cell Lung Cancer (NSCLC) patients and in the characterization of the genetic profile of brain tumours. In this study, 216 EGFR- and 20 ALK-mutated advanced NSCLC patients at progression to first-line treatment with EGFR- or ALK- tyrosine kinase inhibitors (TKIs), and 65 patients affected by brain tumours (64 grade II-IV gliomas and 1 ganglioglioma) were enrolled. Cell free circulating DNA (cfDNA) and exosome-derived RNA were extracted from plasma samples and the quantitative analysis of predictive and prognostic circulating biomarkers (i.e. point mutations in EGFR and ALK genes and PD-L1 mRNA in NSCLC patients or IDH1 and BRAF in brain tumours) was performed by digital droplet PCR. In NSCLC patients the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) osimertinib was effective in patients positive for p.T790M mutation despite at the time of progression to the first line EGFR-TKI treatment the amount in plasma of this resistance mutation resulted much lower than the activating EGFR mutations (p 2.6% and 0.22, respectively (p = 0.01)]. ALK secondary mutations were identified on cfDNA extracted from plasma of NSCLC patients at progression of disease to crizotinib. cfDNA was monitored after the switch of the ineffective therapy to the second-generation ALK inhibitors and the amount of ALK as well as KRAS mutations decreased along with tumour regression. Despite the tumour re-biopsy after progression to EGFR- or ALK TKIs remains a crucial issue for understanding tumour biology and histologic transformation, our study confirms the importance to test in plasma the act-EGFR MAF, T790M/act-EGFR MAF ratio and ALK resistance point mutations as surrogate biomarkers for prognosis and response prediction in NSCLC setting. Interestingly, this study demonstrates that dynamic measurement of PD-L1 expression in plasma-derived exosomes is feasible and may provide useful information on the response to treatment with anti-PD-1 antibodies. Finally, despite the case report described in this study demonstrated that exosomes may be a better vehicle of mutated allele in cerebral tumours compared to cfDNA, allowing the prediction of tumour progression and resistance to treatment, additional prospective studies are needed to evaluate whether circulating biomarkers, integrated with sequential imaging analysis, may improve the management of patients with brain tumour

Unusual gastrointestinal and cutaneous toxicities by bleomycin, etoposide, and cisplatin: A case report with pharmacogenetic analysis to personalize treatment

The standard treatment of testicular germ cell tumors is based on the combination of bleomycin, etoposide, and cisplatin (PEB). However, this treatment may be associated with severe adverse reactions, such as hematological and non-hematological toxicities. Here, we report a case of a patient suffering from severe PEB-related toxicities, to whom pharmacogenetic analyses were performed, comprising a panel of genes involved in PEB metabolism. The analysis revealed the presence of a complex pattern of polymorphisms in GSTP1, UGT1A1 (TA)6/7, UGT1A7, and ABCB1. The present case shows that a pharmacogenetic approach can help in the management of adverse drug reactions in order to predict, prevent, and personalize treatments

Detection of ALK and KRAS Mutations in Circulating Tumor DNA of Patients With Advanced ALK-Positive NSCLC With Disease Progression During Crizotinib Treatment

Background: In patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), disease progression occurs after a median of 9 to 10 months of crizotinib treatment. Several mechanisms of resistance have been identified and include ALK mutations and amplification or the activation of bypassing signaling pathways. Rebiopsy in NSCLC patients represents a critical issue and the analysis of circulating cell-free DNA (cfDNA) has a promising role for the identification of resistance mechanisms. Patients and Methods: Twenty patients with advanced ALK-positive NSCLC were enrolled after disease progression during crizotinib treatment; cfDNA was analyzed using digital droplet polymerase chain reaction (BioRad, Hercules, CA) for ALK (p.L1196M, p.G1269A, and p.F1174L) and Kirsten rat sarcoma (KRAS) (codons 12 and 13) mutations. Results: ALK secondary mutations (p.L1196M, p.G1269A, and p.F1174L) were identified in 5 patients; 1 patient had 2 ALK mutations (p.L1196M and p.G1269A). Overall, 10 patients presented KRAS mutations (7 p.G12D, 2 p.G12V, and 1 p.G12C mutations, respectively). In 3 patients KRAS mutations were associated with ALK mutations. cfDNA was monitored during the treatment with second-generation ALK inhibitors and the amount of ALK as well as KRAS mutations decreased along with tumor regression. Conclusion: ALK and KRAS mutations are associated with acquired resistance to crizotinib in ALK-positive NSCLC. In particular, ALK acquired mutations can be detected in plasma and could represent a promising tumor marker for response monitoring

Concise Review: Resistance to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: The Role of Cancer Stem Cells

Among the potential mechanisms involved in resistance to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), the manifestation of stem-like properties in cancer cells seems to have a crucial role. Alterations involved in the development of TKI resistance may be acquired in a very early phase of tumorigenesis, supporting the hypothesis that these aberrations may be present in cancer stem cells (CSCs). In this regard, the characterization of tumor subclones in the initial phase and the identification of the CSCs may be helpful in planning a specific treatment to target selected biomarkers, suppress tumor growth, and prevent drug resistance. The aim of this review is to elucidate the role of CSCs in the development of resistance to TKIs and its implication for the management of patients

Erratum: Clinical pharmacology of monoclonal antibodies targeting PD-1 axis in urothelial cancers

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Pharmacogenetics of androgen signaling in prostate cancer: focus on castration resistance and predictive biomarkers of response to treatment

Tumor heterogeneity strongly affects the molecular mechanisms driving resistance to hormonal therapies in castration-resistant prostate cancer. Since the current use of available treatments can be optimized on the basis of the molecular profile of tumor, the present review focuses on genetic biomarkers in prostate cancer and their application to a personalized treatment