Warburg Effect And Some Possible Cancer Treatments

The Warburg effect is important in cancer, since cancer cells rely more heavily than do normal cells on glycolysis for energy production.  This may point at therapies targeting this effect for patient benefit.  A paper is here, abstract:

As stated by Otto Warburg nearly a century ago, cancer is a metabolic disease, a fermentation caused by malfunctioning mitochondria, resulting in increased anabolism and decreased catabolism. Treatment should, therefore, aim at restoring the energy yield. To decrease anabolism, glucose uptake should be reduced (ketogenic diet). To increase catabolism, the oxidative phosphorylation should be restored. Treatment with a combination of α-lipoic acid and hydroxycitrate has been shown to be effective in multiple animal models. This treatment, in combination with conventional chemotherapy, has yielded extremely encouraging results in glioblastoma, brain metastasis and lung cancer. Randomized trials are necessary to confirm these preliminary data. The major limitation is the fact that the combination of α-lipoic acid and hydroxycitrate can only be effective if the mitochondria are still present and/or functional. That may not be the case in the most aggressive tumors. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Concomitant correction of this alkalosis may be a very effective treatment in case of mitochondrial failure.

Note that a ketogenic diet is considered one mechanism whereby the Warburg effect can be leveraged for anti-cancer treatment.

Another MicroRNA And Colorectal Cancer

Another microRNA has been shown to affect colorectal cancer, this time by targeting the Wnt pathway-controlling protein APC (that is typically mutated and inactivated in this form of cancer).  The microRNA may promote cancer by further decreasing APC and allowing for more deregulated Wnt signaling.  This has potential diagnostic and therapeutic applications. Abstract:

BACKGROUND:

Aberrant activation of the Wnt/β-catenin signaling pathway is frequently observed in colorectal cancer (CRC). β-catenin is the major Wnt signaling pathway effector and inactivation of adenomatous polyposis coli (APC) results in nuclear accumulation of β-catenin. It has been suggested that inactivation of APC plays an important role in activation of the Wnt/β-catenin pathway and in the progression of colorectal tumorigenesis. However, the mechanism through which APC mediates colorectal tumorigenesis is not understood. Increasing evidence suggests that the dysregulation of microRNAs (miRNAs) is involved in colorectal tumorigenesis. Although miR-494 has been reported as being an upregulated miRNA, the interplay between miR-494 and APC-mediated colorectal tumorigenesis progression remains unclear.

METHODS:

The expression of miR-494 in tissues from patients diagnosed with CRC was analyzed using a microarray and real-time PCR. The effects of miR-494 on cell proliferation and tumorigenesis in CRC cells were analyzed by flow cytometry, colony formation assays, BrdU incorporation assays, and CCK8 assays. The correlation between miR-494 expression and APC expression, as well as the mechanisms by which miR-494 regulates APC in CRC were also addressed.

RESULTS:

miR-494 was significantly upregulated in CRC tissues, and this increase was negatively associated with APC expression. APC was confirmed to be a direct target of miR-494 in CRC. Furthermore, overexpression of miR-494 induced Wnt/β-catenin signaling by targeting APC, thus promoting CRC cell growth.

CONCLUSIONS:

This study provides novel insights into the role of miR-494 in controlling CRC cell proliferation and tumorigenesis, and identifies miR-494 as a potential prognostic marker and therapeutic target.

Mushrooms Against Cancer

Factors from edible and medicinal mushrooms seem to have anti-cancer properties.  These sort of food-based therapies need to be studied better.  Abstract:

Cancer is the leading cause of morbidity and mortality around the globe. For certain types of cancer, chemotherapy drugs have been extensively used for treatment. However, severe side effects and the development of resistance are the drawbacks of these agents. Therefore, development of new agents with no or minimal side effects is of utmost importance. In this regard, natural compounds are well recognized as drugs in several human ailments, including cancer. One class of fungi, "mushrooms," contains numerous compounds that exhibit interesting biological activities, including antitumor activity. Many researchers, including our own group, are focusing on the anticancer potential of different mushrooms and the underlying molecular mechanism behind their action. The aim of this review is to discuss PI3K/AKT, Wnt-CTNNB1, and NF-κB signaling pathways, the occurrence of genetic alterations in them, the association of these aberrations with different human cancers and how different nodes of these pathways are targeted by various substances of mushroom origin. We have given evidence to propose the therapeutic attributes and possible mode of molecular actions of various mushroom-originated compounds. However, anticancer effects were typically demonstrated in in vitro and in vivo models and very limited number of studies have been conducted in the human population. It is our belief that this review will help the research community in designing concrete preclinical and clinical studies to test the anticancer potential of mushroom-originated compounds on different cancers harboring particular genetic alteration(s).

Immune Checkpoint Inhibitor Therapy Biomarkers

Immune checkpoints dampen the immune system’s ability to detect and fight cancer; thus, inhibits of such checkpoints, usually antibodies to checkpoint factors, have utility for immunotherapy against cancer.  Clinical success has been varied, and it would be helpful to identify biomarkers to ascertain what patients would most benefit by this therapeutic approach.  This study identifies some prospective markers that require more conformation.  Abstract:

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel. The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

Against Colitis And Cancer

Chronic inflammation of the colon can increase risk for cancer; an antibody to a pro-inflammatory mediator can reduce inflammation in a mouse model, reducing cancer risk through the modulation of important cancer- related signaling pathways that can be affected by inflammation.  This is a promising therapeutic approach.  Abstract:

The association between chronic inflammation and cancer has long been recognized. The inflammatory bowel disease ulcerative colitis frequently progresses to colon cancer; however, the underlying mechanism is still unclear. S100a9 has been emerged as an important pro-inflammatory mediator in acute and chronic inflammation, and the aberrant expression of S100a9 also contributes to tumorigenic processes such as cell proliferation, angiogenesis, metastasis, and immune evasion. We previously revealed that S100a8 and S100a9 are highly activated and play an important role in the process of colitis-associated carcinogenesis, which suggests an attractive therapeutic target for ulcerative colitis and related colon cancer. Here, we report that administration of a neutralizing anti-S100a9 antibody significantly ameliorated dextran sulfate sodium (DSS)-induced colitis and accompanied by diminished cellular infiltrate of innate immunity cells (macrophages, neutrophils, and dendritic cells) and production of pro-inflammatory cytokines (Tnfα, Il1β, Ifnγ, Il6, Il17a, Il23a, Il4, and Il12a). The protective effect of anti-S100a9 antibody treatment was also observed in azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) mouse model. The inflammatory response, tumor cell proliferation, and immune cells infiltration in the colon tissues were suppressed by anti-S100a9 antibody. Gene expression profiling showed that key pathways known to be involved in CAC development, such as Wnt signaling pathway, PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction, and ECM-receptor interaction pathway, were suppressed after treatment with anti-S100a9 antibody in CAC mice. In view of the protective effect of neutralizing anti-S100a9 antibody against DSS-induced colitis and AOM/DSS-induced CAC in mouse model, this study suggests that anti-S100a9 antibody may provide a novel therapeutic approach to treat ulcerative colitis and may decrease the risk for developing CAC.

Antabuse Against Cancer

The drug Antabuse (disulfram), used as part of alcohol aversion has anticancer properties, with mechanisms described in this paper. Abstract:

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

Leaf Extract Against Colorectal cancer

Here is a study suggesting that Ginkgo biloba L. leaf extract may be beneficial against colorectal cancer by affecting important cell signaling pathways that mediate that disease. The authors state: “The outcomes of the present investigation encourage the use of Ginkgo biloba L. leaf extract as a complementary and alternative therapeutic approach to abate CRC.”  As always consult your own physician; in my opinion, “complementary” may be useful, but “alternative” (as in use this but do not use traditional medical treatments) is a mistake. I have heard of too many horror stories of patients eschewing regular treatment for alternatives and then dying if a curable cancer because they realized, too late, that the alternative was really no alternative at all.  But, again, I am not a medical doctor and I am only giving my own opinion based on scientific background as well as personal experience and anecdote.  I would urge all cancer patients to follow the advice of their oncologists and, of course, ask whether other things can complement treatment.

What's In The Wine?

Resveratrol, which is found in wine as well as in other foodstuffs, has been thought to have a number of positive health benefits.  Here is a study that shows some activity against bone cancer cells.  Certain signaling pathways are involved, including suppression of Wnt signaling. Abstract:

Osteosarcoma is a high-grade bone sarcoma with strong invasive ability. However, treatment with traditional chemotherapeutic drugs is limited by low tolerability and side effects. Resveratrol has been reported previously to have selective antitumor effect on various tumor cells while little is known about its effects and underlying mechanism in osteosarcoma biology. In this study, we found that resveratrol inhibits proliferation and glycolysis, induces apoptosis and reduces the invasiveness of U2-OS cells in vitro. After treatment with resveratrol, the expression of related Wnt/β-catenin signaling pathway target genes, such as β-catenin, c-myc, cyclin D1, MMP-2 and MMP-9, was downregulated and an increased E-cadherin level was observed as well. Additionally, the dual luciferase assay results also indicated that resveratrol suppressed the activity of Wnt/β-catenin signaling pathway. Interestingly, we noticed that the expression of connexin 43 (Cx43) increased with the prolongation of resveratrol treatment time. To further investigate the relationship between Cx43 and the Wnt/β-catenin signaling pathway in osteosarcoma, we used lentiviral-mediated shRNA to knockdown the expression of Cx43. Knockdown of Cx43 activated the Wnt/β-catenin signaling pathway, promoted proliferation and invasion, and inhibited apoptosis of U2-OS cells. Taken together, our results demonstrate that the antitumor activity of resveratrol against U2-OS cells in vitro occurs through up-regulating Cx43 and E-cadherin, and suppressing the Wnt/β-catenin signaling pathway. Moreover, Cx43 expression is negatively related to the activity of the Wnt/β-catenin pathway in U2-OS cells.

Apigenin's Anti-Cancer Properties

The dietary factor apigenin has anti-cancer properties, affecting important cell signaling pathways.  Note this factor is found in many fruits and vegetables, once again showing the importance of those foodstuffs. Also note the comment: “Apigenin appears to have the potential to be developed either as a dietary supplement or as an adjuvant chemotherapeutic agent for cancer therapy.”  Abstract:

Apigenin is a common dietary flavonoid that is abundantly present in many fruits, vegetables and Chinese medicinal herbs and serves multiple physiological functions, such as strong anti-inflammatory, antioxidant, antibacterial and antiviral activities and blood pressure reduction. Therefore, apigenin has been used as a traditional medicine for centuries. Recently, apigenin has been widely investigated for its anti-cancer activities and low toxicity. Apigenin was reported to suppress various human cancers in vitro and in vivo by multiple biological effects, such as triggering cell apoptosis and autophagy, inducing cell cycle arrest, suppressing cell migration and invasion, and stimulating an immune response. In this review, we focus on the most recent advances in the anti-cancer effects of apigenin and their underlying mechanisms, and we summarize the signaling pathways modulated by apigenin, including the PI3K/AKT, MAPK/ERK, JAK/STAT, NF-κB and Wnt/β-catenin pathways. We also discuss combinatorial strategies to enhance the anti-cancer effect of apigenin on various cancers and its use as an adjuvant chemotherapeutic agent to overcome cancer drug resistance or to alleviate other adverse effects of chemotherapy. The functions of apigenin against cancer stem cells are also summarized and discussed. These data demonstrate that apigenin is a promising reagent for cancer therapy. Apigenin appears to have the potential to be developed either as a dietary supplement or as an adjuvant chemotherapeutic agent for cancer therapy.

Problems With Cancer Model Systems

Patient-derived xenografts (PDXs) – where human tumors are transplanted into immunodeficient mice to test for therapeutic approaches – are popular research models in cancer research.  The underlying premise is that the transplanted tissue will “faithfully represent” the original human tumor, but here is a paper suggesting otherwise, showing significant genetic changes that occur.  This of course puts into question how effective the model system is.  It is important to know the limitations of a model system and strive for improvement; it is also important to use the tools at hand.  There is currently no perfect model system for human cancer.  Human cancer cells in culture are a very useful model, but cells in culture are not a human tumor, and the cells of course change over time, so they are not “faithfully representing” the original tumor; various 3-D cell culture models, organoids, etc. are useful but also come with caveats; animal models (transgenics, xenografts, dietary or chemical challenges on wild-type mice) are also useful, but we remember that mice are not humans, and as we see in this paper, transplanted human tissue can change over time.  There is always a hurdle going from therapies tested in model systems to their efficacy in actual human patients, and the variability between models and humans is one major cause for this.  But we must do the best we can with the tools we currently have at hand.  With all their faults, PDXs can yield valuable data; we just need to be careful with the interpretation – and always look toward developing a better model system.  Abstract:

Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of preexisting minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Notably, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have major implications for PDX-based modeling of human cancer.

Biomarkers For Metastatic Colon Cancer Treatment

Metastatic colon cancer patients would benefit from having biomarkers analyzed, to judge potential response to certain therapeutic approaches.  This makes sense, as variation in signaling pathways can affect response to treatments, particularly those that target the altered pathways or other pathways that communicate with those altered.  Abstract:

BACKGROUND:

Metastatic colorectal cancer (mCRC) patients with mutant KRAS or NRAS are ineligible for anti-epidermal growth factor receptor (anti-EGFR) therapy, as RAS mutations activate downstream pathways independently of EGFR and induce primary resistance. However, even among RAS wild-type (WT) patients, only a fraction responds to anti-EGFR therapy, suggesting that other mechanisms of resistance exist. We hypothesise that different (epi)genetic alterations can lead to primary anti-EGFR resistance and that the crucial end point is the activation of protein signalling pathways.

METHODS:

We analysed the expression and activation of proteins involved in cell signalling, using reverse phase protein arrays, on a multicentre French cohort of RAS WT mCRC treated with anti-EGFR treatment.

RESULTS:

We identify activated EGFR and HER3 as protein biomarkers predictive for better overall survival. Active EGFR signalling and downstream PI3K, but not MAPK, pathway activation are associated with response to anti-EGFR treatment. Left-sided mCRC displays active ErbB2/3 and Wnt pathways and a better response to anti-EGFR therapy compared to right-sided mCRC.

CONCLUSIONS:

We identify active EGFR and PI3K signalling as a key factor for response to anti-EGFR treatment in mCRC and highlight the importance of developing these biomarkers in clinical practice for the selection of RAS WT mCRC patients that would benefit from anti-EGFR treatment. British Journal of Cancer advance online publication 12 October 2017; doi:10.1038/bjc.2017.353 www.bjcancer.com.

Bacteria And Chemotherapy Resistance

Bacteria associated with tumors can mediate resistance the chemotherapy drugs. Thus controlling bacterial species in cancer can enhance the efficacy of chemotherapy.  

There is a general pattern emerging from recent research of the importance of bacteria to human other than the simple paradigm of "there's a bacteria infection, give antibiotics." Bacteria we normally carry with us - such as the gut microbiota - affect human health for better or worse, as chronicled at this blog in a number of posts; now we see that human cancer can be associated with bacteria that affect resistance to chemotherapy.

Targeting human-cancer-bacteria interactions seems like a fruitful area of future research.

Nivolumab Vs. Ipilimumab For Melanoma

Nivolumab and ipilimumab are monoclonal antibodies useful in the treatment of advanced melanoma; these target "immune checkpoints" - the activity that suppresses immune system recognition of cancer.  Thus, these antibodies inhibit the checkpoints and allow the patient's immune system to better fight the cancer.  It seems that nivolumab is superior to ipilimumab in at least this study. Abstract:

Background Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. Methods In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. Results At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. Conclusions Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

Why not combine them?  Someone has thought of that, and it works well.

More on checkpoints here.

ANTI-CANCER DRUGS CAN BE COMBINED IN REGIMENS THAT CURE

A combination of  anti-cancer drugs can create a strong fortress against cancer

This note is an afterthought from watching “Surviving terminal cancer” (read here about this documentary) and thinking about the legal hurdles that we have created on our path to cancer therapy and cure.

It is true that we have already developed an impressive arsenal of anti-cancer drugs, and with these we could build treatment regimens that make sense and that exceed the therapeutic potential of any current standard treatments.

So, why are we not doing this? 

According to the documentary: 

(a) the oncologists are not allowed to “combine” anti-cancer drugs in novel (not investigated by clinical trials) regimens even in terminal cancer cases; 

(b) there are rarely clinical trials that combine drugs from different companies, as a successful outcome (profit) from such treatment regimens cannot not be easily “divided” between the companies producing the drugs; 

(c) the current system of clinical trials dictates that any multi-drug combination therapy should be compared to the therapies based upon all possible combinations of the therapeutic components.

Here is a solution: if the patient is terminally ill and there is no reasonable “officially” approved therapy to give any hope, let the oncologist and patient sign a consent that relieves the doctor from any responsibility, but still allows him to assist the patient in his quest to combine drugs and navigate a novel path of treatment.