Tagged: Metformin

The Obesity Paradox, Metformin and Lung Cancer

July 27, 2023

In a new editorial, researchers from Instituto Nacional de Cancerología discuss the obesity paradox and its potential therapeutic opportunities in the context of lung cancer.

The Obesity Paradox, Metformin and Lung Cancer

The strong correlation between obesity and a myriad of life-limiting diseases and conditions, including type 2 diabetes, is widely recognized and acknowledged in the research community. A less defined correlation is that between obesity, diabetes and lung cancer. Whether this association is directly causal or if there are underlying contributing factors is not yet clear.

“Although obesity and type 2 diabetes mellitus (T2DM) have been associated with lung cancer (LC) development, several confounding factors, such as chronic inflammation, high insulin levels, microbiome, as well as the oncogenic potential of growth and sexual hormones, have introduced uncertainty and avoid the fully recognition of this relationship [1, 2].”

Given the existence of this association, scientists are testing therapeutic regimens that may have the potential to fight all three issues — together. Metformin, a drug commonly prescribed to treat type 2 diabetes, helps lower blood sugar levels by improving insulin sensitivity and reducing glucose production in the liver. The metabolic-modifying properties of metformin aid in treating diabetes and obesity. Metformin has also garnered attention for its potential anti-aging properties and may hold promise for treating age-related diseases, including cancer. Lately, there has been growing interest in testing metformin in combination therapies to combat cancer-promoting conditions induced by obesity.

The “Obesity Paradox”

While the link between morbidity and obesity may seem cut-and-dry, researchers have discovered a surprising trend. The “obesity paradox” suggests that, in certain instances, individuals classified as overweight or mildly obese seem to fare better or have a survival advantage compared to those with normal weight or even underweight counterparts. This paradox has been particularly observed in certain chronic illnesses, such as heart failure, chronic kidney disease, and even in the context of aging. Researchers are still striving to understand the underlying mechanisms driving this phenomenon.

In a new editorial, researchers Pedro Barrios-Bernal, Norma Hernández-Pedro, Luis Lara-Mejía, and Oscar Arrieta from Instituto Nacional de Cancerología in Mexico City, Mexico, discuss the obesity paradox and its potential therapeutic opportunities in the context of lung cancer. Their editorial paper was published in Oncotarget on July 1, 2023, and entitled, “Obesity paradox and lung cancer, metformin-based therapeutic opportunity?” They suggest that metformin may have potential therapeutic effects for both obesity and lung cancer. The researchers explore the mechanisms by which metformin may modify tumor metastatic properties and promote an antitumor immune response. They also discuss the potential implications of the obesity paradox in the context of lung cancer treatment and the potential benefits of metformin use in combination with antineoplastic therapies.

In a 2019 study, the researchers conducted a phase 2 randomized clinical trial investigating the effect of metformin combined with tyrosine kinase inhibitors (TKIs) (compared to TKIs alone) in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. They found that the addition of metformin to standard EGFR-TKI therapy in patients with advanced lung adenocarcinoma significantly improved progression-free survival. In their 2022 s tudy, the researchers performed a secondary analysis of the same study, now measuring the association of body mass index (BMI). This time, they reported that the survival outcome in patients with EGFR-mutated lung adenocarcinoma was greater with patients with a BMI higher than 24. The findings suggest that this treatment combination has a selective effect in obese populations and a lack of benefit in patients with a BMI less than 24, thus contributing to the obesity paradox.

“These findings suggest a strong sensitization by the addition of metformin in obese population, suggesting that biochemical and molecular differences influence the treatment response [8].”

Reflections & Future Research

In conclusion, the relationship between obesity, type 2 diabetes and lung cancer remains a subject of ongoing research. Metformin shows promise as a potential multipurpose treatment option, exhibiting properties beneficial for diabetes, obesity, aging, and cancer. The obesity paradox adds a layer of complexity to the obesity-cancer relationship, with some studies suggesting better survival rates and treatment response in overweight or mildly obese individuals treated with metformin. The researchers add that further investigation is needed to determine whether any of the proposed mechanisms of metformin have clinically meaningful activity in the treatment of obese patients with lung cancer. The ongoing research surrounding metformin and its interactions with obesity and cancer may lead to improved therapeutic strategies for these interconnected health challenges.

“Until then, we propose that pharmacodynamics, pharmacokinetics, metabolic parameters, tumor biology, biochemical and molecular modifications may be related to the ‘obesity paradox’ and must be taken into account to choose the most appropriate treatment.”

Click here to read the full editorial in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com. Oncotarget is indexed/archived on MEDLINE / PMC / PubMed.

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Oncotarget

Could Metformin and Rapamycin Replace Maintenance Chemotherapy?

December 16, 2021

Researchers explored metformin with or without rapamycin as maintenance therapy in patients with metastatic pancreatic adenocarcinoma.

Malignant fluid cytology; Malignant cells of adenocarcinoma may spread to fluid of pleural or peritoneal cavity in cancer from the breast, lung, colon, pancreas, ovary, endometrium or other sites. — Malignant cells of adenocarcinoma

Maintenance chemotherapy has previously been recommended for patients with metastatic pancreatic ductal adenocarcinoma (mPDA)—as PDA is an aggressive cancer at all stages, and treatment options are limited for later-stage mPDA. However, maintenance chemotherapy regimens often lead to toxicity and are not viable long-term options. Therefore, researchers are exploring alternative maintenance therapies for mPDA patients. In preclinical studies, the therapeutic combination of metformin and rapamycin demonstrated a potential synergy of anti-tumor activity in PDA.

“A synergistic effect of the combination of metformin with rapamycin was suggested by preclinical studies demonstrating enhanced inhibition of mTOR in a pancreatic cancer cell line and better growth inhibition of pancreatic cancer cells in a xenograft tumor model with the combination than either agent alone [21].”

Metformin is an antihyperglycemic drug that is frequently prescribed for patients with diabetes to help control blood sugar levels. Rapamycin is an immunosuppressive drug that has historically been prescribed to prevent organ rejection in kidney transplant patients. (Today, rapamycin is also being considered for its potential use in anti-aging and longevity interventions.) In animals, metformin and rapamycin both inhibit the major biological regulator of growth, named the mammalian target of rapamycin (mTOR). mTOR is thought to be a main driver of many (if not all) aging-related diseases, including cancers such as PDA.

“Mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase which acts as a signaling node downstream of several oncogenic pathways including KRAS/MEK/ERK and PI3K/Akt, both of which are thought to be relevant drivers in a majority of PDAs [6–9].”

The Study

Given its promising potential, researchers—from Johns Hopkins University School of Medicine, Virginia Piper Cancer Center at HonorHealth, Translational Genomics Research Institute (TGen), and Shanghai Jiao Tong University School of Medicine—conducted a study exploring metformin, plus or minus rapamycin, in patients with metastatic PDA. Their priority research paper was published by Oncotarget in 2020, and entitled, “An exploratory study of metformin with or without rapamycin as maintenance therapy after induction chemotherapy in patients with metastatic pancreatic adenocarcinoma”.

A total of 22 unselected patients with mPDA were included in this randomized open-label phase 1b study between June 2014 and December 2017. Patients were at least 18 years of age and had previously been treated with chemotherapy for mPDA. At the beginning of the study, patients had either stable mPDA or responding mPDA for at least six months after induction chemotherapy. Half of the patients were randomly assigned to study Arm A, and the other 11 patients were assigned to study Arm B. Of note, the average age of the participants in Arm B was older (52–72; 66) than the participants in Arm A (34-73; 58). Otherwise, baseline characteristics between the study groups were relatively well-balanced.

Participants in study Arm A were assigned to take 850 milligrams of metformin orally, two times per day, for at least 12 months. Participants in study Arm B were assigned to take metformin and four milligrams of rapamycin once per day, for at least 12 months. The researchers conducted PET/CT scans, immunologic and metabolic analyses, statistical analysis, and continuously recorded and monitored for safety, patient tolerance, toxicity, and treatment-related adverse events.

“Treatment was continued until disease progression, intolerance of study treatments, or study closure, which occurred only after all remaining patients received a minimum of 12 months of treatment.”

Results and Conclusion

“In conclusion, the administration of metformin with or without rapamycin in patients with mPDA who achieve a response to chemotherapy is well-tolerated and was associated with better than expected overall survival in this study.”

The researchers observed “remarkably longer than expected” progression free survival and overall survival in this typically poor-prognosis population of patients. In this cohort, a low neutrophil-to-lymphocyte ratio and decreased fluorodeoxyglucose-avidity and/or decreased CA19-9 from baseline predicted improved outcomes among the long-term survivors. Overall, metformin and rapamycin were well-tolerated and their safety profiles were found to be comparable to previous reports. The researchers were forthcoming about limitations of their study—as their cohort was relatively small and the study was not powered to detect differences in clinical activity between the treatment arms.

“To this end, we identified several factors which may be used to select for patients with improved outcomes; however, whether good prognosis patients need any further treatment at all and whether poor prognosis patients will benefit from continued chemotherapy rather than a maintenance approach are not known and additional prospective studies are needed to answer these questions.”

Click here to read the full priority research paper, published by Oncotarget.

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Mikhail Blagosklonny

Are Anti-aging Drugs the Key to Cancer Prevention?

February 4, 2021

In his recent paper, Dr. Mikhail Blagosklonny explains his perspective on the current landscape of anti-aging drug studies, a key differentiation between healthspan and lifespan variables, and the next steps for human use of anti-aging drugs—beyond clinical trials.

Aging in humans seems as natural as aging in leaves—but is it necessary?

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The process of human aging is a fascinating mystery. Despite all that we do not know, a handful of researchers have dedicated recent decades to the exciting beginnings of solving this biological riddle. One such researcher is Dr. Mikhail Blagosklonny. As a professor of oncology at the Roswell Park Cancer Institute in Buffalo, New York, and Editor-in-Chief at the AgingandOncotarget journals, Dr. Blagosklonny’s mission is to prevent cancer (and other age-related diseases) by inhibiting the aging process—preventing cancer by maintaining youth.

The cover paper chosen for Oncotarget’s Volume 12, Issue #3, is titled, “The goal of geroscience is life extension;” a research perspective written by Dr. Blagosklonny. In this compelling paper, he reflects on the history of anti-aging studies, the differences between drugs that enhance healthspan versus lifespan, and next steps in the human application of anti-aging drugs.

Hyperfunction Theory of Aging

“According to the geroscience hypothesis, aging is a risk factor for diseases [127]. According to hyperfunction theory, in contrast, aging is a sum of all age-related diseases, not their risk factors.”

Dr. Blagosklonny defines aging as a continuation of human development, driven partially by growth-promoting pathways which drive age-related diseases—he has coined this as the hyperfunction theory.

“Hyperfunction (inappropriate activation) of these signaling pathways directly drive all age-related diseases, which are manifestations of aging. We just need clinically available inhibitors (drugs) of these signaling pathways to extend both healthspan and lifespan, by slowing aging.”

Increasing Lifespan via Increasing Healthspan

Before beginning his interpretation of data from previous anti-aging research studies, Dr. Blagosklonny emphasises the importance of correctly measuring healthspan and lifespan. As indicated in his paper title, the goal of geroscience is to extend lifespan by way of extending overall healthspan.

“Healthspan is a period of life without age-related diseases [27]. It is disease-free survival.”

Healthspan can be difficult to measure due to the nature and hidden course of many diseases. If one particular disease is subdued by treatment in a study and healthspan appears to be increased (through one marker of health or another), this does not guarantee that other age-related diseases have been nullified by this treatment. Dr. Blagosklonny explains that accurate measurements of healthspan are important because, based on the hyperfunction theory, aging is the sum of all age-related diseases.

“After all, aging is an exponential increase of death with age and should be measured by deadly diseases.”

Another point he makes is that many anti-aging drug trials have presented results finding increased healthspan in mice without demonstrating an increase in lifespan. Given that increased healthspan should always lead to increased lifespan, it is not sufficient to only measure healthspan without measuring lifespan in animal studies of anti-aging drugs. If lifespan is not increased, the drug does not demonstrate longevity or anti-aging properties.

“So how is it possible that some senolytics, NAD boosters and resveratrol, increase healthspan without lifespan? The simplest explanation is that they do not increase healthspan at all, because such studies use irrelevant or ambiguous markers of health.”

Over the years, numerous initially promising anti-aging drugs have been tested and debunked by researchers. No compound has continued to withstand the many tests, or has delivered consistent results, quite like the unique bacterium, rapamycin.

Anti-aging Properties in Rapamycin

Rapamycin was discovered in 1964 in a test tube sample of dirt taken from Easter Island—a highly remote volcanic island in the Pacific ocean, west of Chile. Initially looking for antibiotics (often uncovered in the dirt) researchers found the rapamycin bacteria unexpectedly. To their surprise, this new bacteria created a defensive chemical with the ability to affect the activity of a protein and homeostatic ATP sensor called the mammalian target of rapamycin, or mTOR. mTOR is now known to function in regulatory pathways that are responsible for governing cell growth.

“It was predicted that rapamycin must extend lifespan before it was shown in any animal [105].”

In 1999, rapamycin was FDA approved to regulate hyperimmunity in transplant patients to help enable their immune system to accept a new organ. Since then, rapamycin’s ability to slow cell growth and proliferation has been widely accepted as an anticancer agent and the focus of anti-aging studies in a number of mouse-modeled trials.

“Since 2009, dozens of studies have shown that rapamycin extends medium and maximum lifespan in both males and females in all strains of normal mice tested, as well as in some cancer-prone and short-lived mice [36, 40–70].

Other Drugs With and Without Anti-aging Potential

In this paper, Dr. Blagosklonny categorizes a list of seemingly debunked anti-aging drugs with little or no results, including antioxidants, resveratrol, curcumin, quercetin (used alone), and spermidine. He explains that some of these drugs may have potential when used in combination with other drugs in future studies.

He acknowledges potential in berberine (one study found promising initial results), fisetin (clinically available and safe for human use), 17-alpha-estradiol (only results in male mice thus far), acarbose (blocks digestion of complex carbs), enalapril (decreases oxidative damage), losartan (angiotensin receptor blocker), quercetin with dasatinib (clinically available and safe for human use), and metformin.

“Some life-extending drugs are already approved for human use: supplements (fisetin, vitamin B3 and its analogs), over-the-counter medicine (aspirin) and prescription drugs (rapamycin, metformin, dasatinib, enilopril).”

Dr. Blagosklonny recalls a famous study of metformin where, at a low doses, it increased lifespan in male mice and, at high doses, it ironically decreased lifespan. Metformin was also tested with rapamycin in this study and demonstrated improved results in extending lifespan.

“Yet, a combination of metformin and rapamycin should be re-tested to include a rapamycin-alone group.”

Conclusion

“I expect that a combination of low doses of pan-mTOR and MEK inhibitors with high doses of rapamycin would extend life further compared with rapamycin alone. That could be the next important advance in the anti-aging field since the discovery of anti-aging properties of rapamycin.”

Dr. Blagosklonny believes that researchers should not wait for the lifespan results of clinical trials in humans to begin widespread application of these drugs, since studies already safely display increased lifespan and longevity in mouse models. He is so convinced by rapamycin that Dr. Blagosklonny is currently taking 10 milligrams of rapamycin per week along with his personalized treatment plan, a ketogenic diet, and exercise to jumpstart the next phase of human anti-aging trials within our lifetime. He notes that medical doctors interested in this topic may email Blagosklonny@rapalogs.com or follow him on Twitter @Blagosklonny.

“This article does not represent medical advice or recommendations to patients. The media should exercise caution and seek expert medical advice for interpretation when referring to this article.”

Click here to read the full research perspective on Oncotarget.com.

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Oncotargetis a unique platform designed to house scientific studies in a journal format that is available for anyone to read—without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues, and other researchers, far and wide.

For media inquiries, please contact media@impactjournals.com.