Wnt Inhibitor And Small Cell Lung Cancer

A Wnt signaling inhibitor has some activity against small cell lung cancer.  Abstract:

Small cell lung cancer (SCLC) is the most aggressive type of lung cancer due to a fast tumor doubling time and early hematogenous spread. Advances in the treatment of non-small cell lung cancer using targeted therapies having been made, but no targeted drugs for SCLC have been approved. The Wnt signaling pathway is associated with tumor progression and metastasis; therefore, the inhibition of Wnt/β-catenin signaling is a strategy for anticancer drugs. Tankyrase 1 (TNKS1) is overexpressed in a number of types of cancer and XAV939 is a small molecule inhibitor of TNKS1 which may inhibit tumor growth. The present study aimed to investigate the potential molecular mechanisms underlying XAV939-induced suppression of the viability of SCLC cells. MTT assays were used to determine the viability-inhibition rate of cells and to identify the drug concentration which optimally inhibited cell viability. Flow cytometry was used to determine whether XAV939 induced apoptosis of SCLC cells, and to analyze the effect of the drug on the cell cycle. The results of the present study identified that XAV939 inhibited the viability of NCI-H446 cells in a dose-dependent manner, but cisplatin inhibited NCI-H446 cell viability in a time- and dose-dependent manner. The combination of XAV939 and cisplatin exhibited a slightly more pronounced inhibition of cell viability at an increased dose of XAV939. In addition, XAV939 markedly induced cell apoptosis of the SCLC cell line H446 by increasing the proportion of cells in the G0/G1 phase, leading to inhibition of the cell cycle. The results of the present study indicated that XAV939 inhibited the viability of the NCI-H446 SCLC cell line by inducing cell apoptosis through the Wnt signaling pathway. Therefore, XAV939 may be useful for the treatment of SCLC.

Different Roles Of Dkk1 In Cancer Metastasis

Wnt signaling is involved in the development and progression of a variety of cancers, and researchers have typically approached Wnt-targeted therapeutics with the aim of suppressing this signaling. Dkk1 is an inhibitor of Wnt signaling, and so this molecule has been thought to be useful with respect to cancer therapy.  But in the paper linked here, it was shown that while Dkk1 inhibits metastasis of lung cancer, it can actually promote metastasis of breast cancer to bone.  This demonstrates that particular therapeutic approaches may need to be specifically targeted to particular cancer types; it also suggests that suppression of signaling is not always the best approach.  There has been some work suggesting boosting cell signaling to abnormally high levels can cause cancer cell death as well; this is a topic worth revisiting in the future.  Abstract:

Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca2+-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.

Osimertinib Against Lung Cancer

Osimertinib is a relatively new molecularly-targeted anti-cancer therapy that targets EGF signaling, and has shown efficacy for EGFR mutation-positive advanced non-small-cell lung cancer. Abstract:

Background Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Methods In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. Results The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). Conclusions Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).

Vitamin B Supplementation May Increase Lung Cancer Risk In Men

There is sometimes a "more is better" attitude that some people have towards vitamins, particularly vitamin supplements,  and that can be dangerous, as some vitamins can be harmful, even dangerous, with taken excessively. Getting vitamins in foods rather than in supplements is, when it is possible, usually preferable.  The article linked here suggests that vitamin B supplements, in this case vitamins B6 and B12, can increase lung cancer risk in men, particularly for male smokers.  Both patients and their doctors should be aware of these findings, and physicians should advise their patients, especially those at higher risk, accordingly.  Abstract:

Purpose Inconsistent findings have been reported of a link between the use of one-carbon metabolism-related B vitamins and lung cancer risk. Because of the high prevalence of supplemental vitamin B use, any possible increased association warrants further investigation. We examined the association between long-term use of supplemental B vitamins on the one-carbon metabolism pathway and lung cancer risk in the Vitamins and Lifestyle (VITAL) cohort, which was designed specifically to look at supplement use relative to cancer risk. Methods A total of 77,118 participants of the VITAL cohort, 50 to 76 years of age, were recruited between October 2000 and December 2002 and included in this analysis. Incident, primary, invasive lung cancers (n = 808) were ascertained by prospectively linking the participants to a population-based cancer registry. The 10-year average daily dose from individual and multivitamin supplements were the exposures of primary interest. Results Use of supplemental vitamins B6, folate, and B12 was not associated with lung cancer risk among women. In contrast, use of vitamin B6 and B12 from individual supplement sources, but not from multivitamins, was associated with a 30% to 40% increase in lung cancer risk among men. When the 10-year average supplement dose was evaluated, there was an almost two-fold increase in lung cancer risk among men in the highest categories of vitamin B6 (> 20 mg/d; hazard ratio, 1.82; 95% CI, 1.25 to 2.65) and B12 (> 55µg/d; hazard ratio, 1.98; 95% CI, 1.32 to 2.97) compared with nonusers. For vitamin B6 and B12, the risk was even higher among men who were smoking at baseline. In addition, the B6 and B12 associations were apparent in all histologic types except adenocarcinoma, which is the type less related to smoking. Conclusion This sex- and source-specific association provides further evidence that vitamin B supplements are not chemopreventive for lung cancer and may be harmful.

Alzheimer's Disease-Cancer Link

First described case of Alzheimer's disease. By Unknown - Unknown, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1595297

Sometimes serious diseases have interesting co-morbidities.  Having one disease may increase or decrease your risk of getting the other.  Such co-morbidities exist between some nervous system diseases and some forms of cancer.  Not surprisingly, Alzheimer’s disease and brain cancer are positively linked, which may be due to common changes in immune function affecting brain cells, while Alzheimer’s and lung cancer are negatively associated.  It seems that changes in the mitochondria – “the powerhouse of the cell” – that increase the risk of Alzheimer’s decrease the risk of lung cancer and vice versa.  Studying the mechanisms behind such correlations can lead to new therapies for these diseases.  From the article:

Alzheimer’s disease, lung cancer, and brain cancer—all devastating, all leading public health challenges—have been thought to harbor connections at the molecular level, connections that could explain curious co-morbidities. Specifically, in cases of Alzheimer’s disease, the risk of developing lung cancer is decreased, and the risk of developing glioblastoma, a kind of brain tumor, is increased…

…“A functional analysis of the sets of deregulated genes points to the immune system, up-regulated in both Alzheimer’s disease and glioblastoma, as a potential link between these two diseases,” wrote the article’s author. “Mitochondrial metabolism is regulated oppositely in Alzheimer’s disease and lung cancer, indicating that it may be involved in the inverse co-morbidity between these diseases.”

The authors of the current paper emphasized that they intended to explain previously published findings that overexpressed genes in central nervous system diseases (Alzheimer's disease, Parkinson's disease, and schizophrenia) were underexpressed in cancer (lung, colon, and prostate), and vice versa. Understanding the molecular bases of these processes, the authors suggested, could provide valuable information regarding the study of the causes of each disease and the possible design of new therapeutic strategies (drug repositioning).

Carbs and Cancer: Glycaemic Index and Lung Cancer

Is eating certain carbs as bad as smoking?

PITTSBURGH (KDKA) – You’ve heard that carbs can increase your waistline, but according to a new study they could be as bad for you as smoking cigarettes.
 

The study found carbs can actually raise the risk of lung cancer by some 49-percent.
 
Scientists found foods with a high glycaemic index, such as white bread, may increase the risks of cancer.
 
The report says glycaemic index is a measure of the quality of dietary carbohydrates – and is defined by how certain foods affect our blood sugar levels after eating.
 
The theory behind the study is that high-GI foods trigger higher levels of glucose and insulin in the blood, which in turn increase Insulin-Like Growth Factors (IGFs).
 
The study was conducted by the University of Texas MD Anderson Cancer Center.
 
Lead author on the study, Dr. Stephanie Melkonian says: “We observed a 49 percent increased risk of lung cancer among subjects with the highest daily GI compared to those with the lowest daily GI.”
 
The study says people should limit their intake of foods and beverages with a high GI.

So, in this study is was not total carbs per se that was the problem, but rather, the type of carbs - in other words a qualitative rather than strictly quantitative problem. Therefore, "white" and "starchy" carbs are a problem, by causing blood glucose spikes that result in higher levels of insulin and insulin-like growth factors. Whole wheat, etc, as much as non-starchy vegetables and many fruits, do not have the same effect. Although the problem is qualitative in that the type of carbs is what's most important, of course how much you eat of it will influence risk. Eating some occasional white bread and rice (which I for one try to avoid as much as possible) is likely not going to be as risky as stuffing your face with it every day, especially multiple times per day. Eating some potatoes won't kill you either. Again, it is a question of balance. For a variety of reasons independent of this study (obesity, diabetes, etc.) it is a good idea to limit levels of high glycaemic carbs. One does not have to completely eliminate them, but limit consumption , definitely, yes.