NAD pool as an antitumor target against cancer stem cells in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that affect different anatomical locations. Despite this heterogeneity, HNSCC treatment depends on the anatomical location, TNM stage and resectability of the tumor. Classical chemotherapy is based on platinum-derived drugs (cisplatin, carboplatin and oxaliplatin), taxanes (docetaxel, paclitaxel) and 5-fluorouracil1. Despite advances in HNSCC treatment, the rate of tumor recurrence and patient mortality remain high. Therefore, the search for new prognostic identifiers and treatments targeting therapy-resistant tumor cells is vital. Our work demonstrates that there are different subgroups with high phenotypic plasticity within the CSC population in HNSCC. CD10, CD184, and CD166 may identify some of these CSC subpopulations with NAMPT as a common metabolic gene for the resilient cells of these subpopulations. We observed that NAMPT reduction causes a decrease in tumorigenic and stemness properties, migration capacity and CSC phenotype through NAD pool depletion. However, NAMPT-inhibited cells can acquire resistance by activating the NAPRT enzyme of the Preiss-Handler pathway. We observed that coadministration of the NAMPT inhibitor with the NAPRT inhibitor cooperated inhibiting tumor growth. The use of an NAPRT inhibitor as an adjuvant improved NAMPT inhibitor efficacy and reduced the dose and toxicity of these inhibitors. Therefore, it seems that the reduction in the NAD pool could have efficacy in tumor therapy. This was confirmed by in vitro assays supplying the cells with products of inhibited enzymes (NA, NMN or NAD) and restoring their tumorigenic and stemness properties. In conclusion, the coinhibition of NAMPT and NAPRT improved the efficacy of antitumor treatment, indicating that the reduction in the NAD pool is important to prevent tumor growth.

Senotherapeutics in Cancer and HIV.

Cellular senescence is a stress-response mechanism that contributes to homeostasis maintenance, playing a beneficial role during embryogenesis and in normal adult organisms. In contrast, chronic senescence activation may be responsible for other events such as age-related disorders, HIV and cancer development. Cellular senescence activation can be triggered by different insults. Regardless of the inducer, there are several phenotypes generally shared among senescent cells: cell division arrest, an aberrant shape, increased size, high granularity because of increased numbers of lysosomes and vacuoles, apoptosis resistance, defective metabolism and some chromatin alterations. Senescent cells constitute an important area for research due to their contributions to the pathogenesis of different diseases such as frailty, sarcopenia and aging-related diseases, including cancer and HIV infection, which show an accelerated aging. Hence, a new pharmacological category of treatments called senotherapeutics is under development. This group includes senolytic drugs that selectively attack senescent cells and senostatic drugs that suppress SASP factor delivery, inhibiting senescent cell development. These new drugs can have positive therapeutic effects on aging-related disorders and act in cancer as antitumor drugs, avoiding the undesired effects of senescent cells such as those from SASP. Here, we review senotherapeutics and how they might affect cancer and HIV disease, two very different aging-related diseases, and review some compounds acting as senolytics in clinical trials.

Therapeutic Targeting of Signaling Pathways Related to Cancer Stemness.

The theory of cancer stem cells (CSCs) proposes that the different cells within a tumor, as well as metastasis deriving from it, are originated from a single subpopulation of cells with self-renewal and differentiation capacities. These cancer stem cells are supposed to be critical for tumor expansion and metastasis, tumor relapse and resistance to conventional therapies, such as chemo- and radiotherapy. The acquisition of these abilities has been attributed to the activation of alternative pathways, for instance, WNT, NOTCH, SHH, PI3K, Hippo, or NF-κB pathways, that regulate detoxification mechanisms; increase the metabolic rate; induce resistance to apoptotic, autophagic, and senescence pathways; promote the overexpression of drug transporter proteins; and activate specific stem cell transcription factors. The elimination of CSCs is an important goal in cancer therapeutic approaches because it could decrease relapses and metastatic dissemination, which are main causes of mortality in oncology patients. In this work, we discuss the role of these signaling pathways in CSCs along with their therapeutic potential.

New markers for human ovarian cancer that link platinum resistance to the cancer stem cell phenotype and define new therapeutic combinations and diagnostic tools.

BACKGROUND: Ovarian cancer is the leading cause of gynecologic cancer-related death, due in part to a late diagnosis and a high rate of recurrence. Primary and acquired platinum resistance is related to a low response probability to subsequent lines of treatment and to a poor survival. Therefore, a comprehensive understanding of the mechanisms that drive platinum resistance is urgently needed. METHODS: We used bioinformatics analysis of public databases and RT-qPCR to quantitate the relative gene expression profiles of ovarian tumors. Many of the dysregulated genes were cancer stem cell (CSC) factors, and we analyzed its relation to therapeutic resistance in human primary tumors. We also performed clustering and in vitro analyses of therapy cytotoxicity in tumorspheres. RESULTS: Using bioinformatics analysis, we identified transcriptional targets that are common endpoints of genetic alterations linked to platinum resistance in ovarian tumors. Most of these genes are grouped into 4 main clusters related to the CSC phenotype, including the DNA damage, Notch and C-KIT/MAPK/MEK pathways. The relative expression of these genes, either alone or in combination, is related to prognosis and provide a connection between platinum resistance and the CSC phenotype. However, the expression of the CSC-related markers was heterogeneous in the resistant tumors, most likely because there were different CSC pools. Furthermore, our in vitro results showed that the inhibition of the CSC-related targets lying at the intersection of the DNA damage, Notch and C-KIT/MAPK/MEK pathways sensitize CSC-enriched tumorspheres to platinum therapies, suggesting a new option for the treatment of patients with platinum-resistant ovarian cancer. CONCLUSIONS: The current study presents a new approach to target the physiology of resistant ovarian tumor cells through the identification of core biomarkers. We hypothesize that the identified mutations confer platinum resistance by converging to activate a few pathways and to induce the expression of a few common, measurable and targetable essential genes. These pathways include the DNA damage, Notch and C-KIT/MAPK/MEK pathways. Finally, the combined inhibition of one of these pathways with platinum treatment increases the sensitivity of CSC-enriched tumorspheres to low doses of platinum, suggesting a new treatment for ovarian cancer.

MAP17 (PDZK1IP1) and pH2AX are potential predictive biomarkers for rectal cancer treatment efficacy.

Rectal cancer represents approximately 10% of cancers worldwide. Preoperative chemoradiotherapy increases complete pathologic response and local control, although it offers a poor advantage in survivorship and sphincter saving compared with that of radiotherapy alone. After preoperative chemoradiotherapy, approximately 20% of patients with rectal cancer achieve a pathologic complete response to the removed surgical specimen; this response may be related to a better prognosis and an improvement in disease-free survival. However, better biomarkers to predict response and new targets are needed to stratify patients and obtain better response rates. MAP17 (PDZK1IP1) is a small, 17 kDa non-glycosylated membrane protein located in the plasma membrane and Golgi apparatus and is overexpressed in a wide variety of human carcinomas. MAP17 has been proposed as a predictive biomarker for reactive oxygen species, ROS, inducing treatments in cervical tumors or laryngeal carcinoma. Due to the increase in ROS, MAP17 is also associated with the marker of DNA damage, phosphoH2AX (pH2AX). In the present manuscript, we examined the values of MAP17 and pH2AX as surrogate biomarkers of the response in rectal tumors. MAP17 expression after preoperative chemoradiotherapy is able to predict the response to chemoradiotherapy, similar to the increase in pH2AX. Furthermore, we explored whether we can identify molecular targeted therapies that could help improve the response of these tumors to radiotherapy. In this sense, we found that the inhibition of DNA damage with olaparib increased the response to radio- and chemotherapy, specifically in tumors with high levels of pH2AX and MAP17.