Tagged: Non-Small Cell Lung Cancer

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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Trending With Impact: Analysis of Mutational Burden in NSCLC

April 21, 2022

Researchers conducted a multi-site cohort study of tumor mutational burden among hundreds of patients diagnosed with stage IV non-small cell lung cancer (NSCLC).

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While a high tumor mutational burden (TMB) may seem unfavorable in the midst of battling non-small cell lung cancer (NSCLC), a higher TMB has been associated with a higher number of neoantigens. The presence of more neoantigens can potentially elicit a stronger immune response. Therefore, TMB may be a viable biomarker of tumor response to immunotherapeutic agents. However, the definitions, parameters and units used to measure high- and low-TMB have been inconsistent over the years. Today, the consensus unit for reporting TMB has shifted to mutations per megabase (mut/Mb). The common cut-off for high- vs. low-TMB from tissue samples is >10 mut/Mb in NSCLC.

“Despite inconsistencies with TMB definition and reporting over time, high TMB has consistently been associated with improved clinical benefit among patients receiving immunotherapy for NSCLC [22].”

Researchers—from University of Utah, University of Minnesota Duluth, Huntsman Cancer Institute, H. Lee Moffitt Cancer Center and Research Institute, Baptist Health Medical Group, MetroHealth Medical Center, Rutgers Cancer Institute of New Jersey, University of Southern California, Saint Luke’s Cancer Institute, University of Kentucky, and Bristol Myers Squibb—used the newest consensus unit and common cut-off parameters for TMB expression to measure TMB’s relationship to treatment response and survival outcomes among metastatic NSCLC patients. Their trending research paper was published in Oncotarget’s Volume 13 on January 31, 2022, and entitled, “Real-world survival analysis by tumor mutational burden in non-small cell lung cancer: a multisite U.S. study.”

“The purpose of this study is to evaluate clinical outcomes by TMB among NSCLC patients treated with immunotherapy containing regimens in the first-line setting.”

The Study

Participants in this large cohort study included 667 patients who had been diagnosed with stage IV NSCLC and treated with any NSCLC-related treatment. Patients were recruited from nine different academic and community cancer centers across the United States. The researchers intended to utilize this “real-world” dataset and hoped it would allow them to realistically assess the role of TMB as a potential biomarker of NSCLC response to treatment.

First, the team collected demographic and clinical characteristics and separated them into two groups: TMB greater or less than 10 mut/Mb. Characteristics included age, sex, race, body mass index, smoking history, PD-L1 expression, comorbidities, Eastern Cooperative Oncology Group performance status (ECOG PS) at diagnosis, histology subtype, Stage at metastatic diagnosis, and site of metasteses. Interestingly, a history of smoking was significantly associated with a TMB greater than 10 mut/Mb.

“Smoking status was significantly associated with TMB >10 with 91% of patients reported as current or former smokers compared to 61% in the TMB <10 cohort (p < 0.01, Table 1).”

The Results

The researchers found no association between TMB and age, PD-L1 expression, tumor histology, or cancer stage at diagnosis. Next, the team assessed for significant associations between TMB and 17 genomic alterations. They found that lower TMB was associated with ALK and EGFR alterations. Higher TMB was associated with TP53 alterations. The researchers investigated the association between TMB and treatment patterns and responses. The overall response rate was very similar in both groups.

A multivariable model was used to analyze overall patient survival and progression-free survival (PFS) for first-line immunotherapy containing regimens based on TMB. The model controlled for the initial patient characteristics and did not demonstrate significantly different results for overall survival in the two groups. However, the researchers found in a subgroup analysis that, of the patients who received TMB testing within 60 days of receiving immunotherapy treatment, those with TMB >10 demonstrated significantly longer overall survival compared to their TMB <10 counterparts. In terms of PFS, they found that PFS was longer among patients with TMB >10 in the cohort and subgroup analyses. PFS was significantly longer when treated with an immunotherapy-containing regimen first-line compared to a first-line treatment of chemotherapy. An association between TMB and PD-L1 expression was not found in this study.

Conclusion

“This study evaluated two broad questions: (1) The distribution of TMB in the real world and its association with baseline clinical and demographic features (n = 677) and (2) the association between TMB and clinical outcomes among NSCLC patients who received first-line immunotherapy (n = 224).”

Results of the study confirmed the association between a higher TMB and smoking history, as well as the benefits of first-line immunotherapy within two months of TMB testing. While the researchers were forthcoming about limitations in their study, metastatic NSCLC patients with TMB>10 who were treated with first-line immunotherapy had improved overall survival and progression-free survival.

“Based on the results in this study and prior research, TMB along with other biomarkers, such as PD-L1, may help identify patients more likely to benefit from first-line immunotherapy.”

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

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New Study: ALK Rearrangement Among Lung Cancer Patients

November 10, 2021

In Oncotarget’s Volume 12, Issue 23, cover paper, researchers retrospectively assessed the prevalence of anaplastic lymphoma kinase (ALK) gene rearrangement among nearly 20,000 patients with advanced non-small cell lung cancer.

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The identification of an actionable gene mutation or translocation in patients with cancer can give researchers a target for new drug therapies. One such mutation, found in some patients with non-small cell lung cancer (NSCLC), is anaplastic lymphoma kinase (ALK) gene rearrangement. However, the exact population of patients that present with ALK rearrangement has not been fully characterized. Identifying the subpopulation of patients who present with ALK rearrangement may lead to better overall treatment outcomes.

Researchers—from University of Mississippi Medical Center, Roche Information Solutions, Roche Diagnostics Corporation, Genesis Research, and Houston Methodist Hospital—conducted a retrospective study of nearly 20,000 patients with advanced NSCLC (aNSCLC). The researchers assessed ALK rearrangement prevalence in the cohort overall and then categorized the data using patient characteristics. Their paper was published on the cover of Oncotarget’s Volume 12, Issue 23, and entitled, “Anaplastic lymphoma kinase rearrangement prevalence in patients with advanced non-small cell lung cancer in the United States – retrospective real world data”.

“We performed a retrospective study of a database to acquire real-world clinical data on the frequency of the translocation in a large pool of patients drawn primarily from community hospitals and practices.”

The Study

This cross-sectional, observational study used de-identified data from Flatiron Health’s database, which included 19,895 patients who were diagnosed with aNSCLC in the United States between 2015 and 2019. The average age of patients was 68.5, plus or minus 10 years. The distribution of gender was nearly equal, with men comprising 50.4% (10,029) of the patient cohort, and 68.4% of patients were Caucasian. A large proportion of patients had a non-squamous histology type (80.5%) and smoking history (85.5%).

“Prevalence of ALK rearrangement was assessed overall and then stratified by patient characteristics such as age, gender, race, smoking status and histology.”

The researchers used descriptive statistics to summarize patient characteristics. Characteristics included age, gender, race, geographic location, smoking status, histology, practice type (community or academic), PD-L1 status, prevalence of ALK rearrangement and other biomarkers.

“Regardless of documented histology, a higher ALK rearrangement rate (8.9%) was observed among patients who had no smoking history compared to patients with a smoking history (1.5% ALK positivity) which represent the largest number of patients in this cohort (17,003).”

Conclusion

Results from the study concluded that ALK rearrangement was present in 2.6% of the total cohort, or 517 patients. The researchers found that ALK rearrangement prevalence varied based on the patients’ demographic characteristics. The rate of ALK rearrangement was the highest among patients younger than 40 years old, and decreased with age. Researchers found no significant difference in ALK rearrangement between men and women. However, when compared to other patients, Asian patients had a higher ALK rearrangement rate (39 out of 623, or 6.3%). Interestingly, the ALK positivity rate was greatest (9.3%) among non-smoking patients with non-squamous histology.

“In summary, this retrospective review of nearly 20,000 patients with aNSCLC and tested for ALK in the United States confirms that ALK rearrangements are found more commonly in younger nonsmokers and patients of Asian descent.”

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

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Trending With Impact: Unconventional Method Effectively Targets NSCLC

October 4, 2021

Researchers developed a divergent strategy to treat non-small cell lung cancer (NSCLC).

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The mammalian target of rapamycin (mTOR) operates within two distinct protein complexes—mTOR complex 1 (mTORC1) and complex 2 (mTORC2). These protein complexes are not yet fully understood, as they were only recently identified in humans in 1994. What researchers do know is that mTORC1 is involved in the regulation of many cellular processes and is a key mediator of cell growth and proliferation. mTORC1 is activated by growth factor receptor signals through the PI3K–AKT and RAS–ERK mitogen-activated protein kinase (MAPK) pathways.

The PI3K/AKT/mTOR pathway may be an efficacious target in the treatment of patients with non-small cell lung cancer (NSCLC). This theory is based on the identification of particular gene mutations in NSCLC that are associated with the PI3K/AKT/mTOR pathway. However, previous studies have not yet succeeded in defining an effective monotherapy or combination of therapies that targets this pathway while improving NSCLC patient outcome.

Researchers from Institut Curie, PSL University, Xentech, BioPôle Alfort, Hôpital Foch, and Centre Léon Bérard designed a study using a new methodology to test treatment combinations based on specific targets identified as biomarkers of resistance to PI3K-targeting treatments, and not based on the NSCLC mutations themselves. Their trending research paper was published by Oncotarget in 2021 and entitled, “High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.”

“Our main strategy was therefore, using a panel of NSCLC PDXs, (i) to define predictive markers of response to RAD001 therapy and (ii) to identify possible combinations of treatments that may be able to reverse RAD001 resistance.”

THE STUDY

Researchers tested RAD001/Everolimus (an mTORC1 inhibitor) in vivo using NSCLC Patient-Derived Xenografts (PDXs), which demonstrated high antitumor efficacy. They next aimed to define predictive markers of response to RAD001 using real-time quantitative RT-PCR assays.

“In order to define predictive markers of response to RAD001, we used real-time quantitative RT-PCR assays to quantify the mRNA expression of a large number of selected genes.”

The team found three significantly highly expressed and targetable genes in NSCLC tumors resistant to RAD001: PLK1, CXCR4 and AXL. They then analyzed these genes for their prognostic value among NSCLC patients that were found in the publicly available database KMPLOT. This analysis revealed that of the three genes evaluated, only one high-gene expression was correlated with a negative impact on overall survival of patients with adenocarcinoma: PLK1. Given this data, the researchers next evaluated the in vivo efficacy of RAD001 combined with a PLK1 inhibitor, volasertib, in four PDX models. The RAD001 + volasertib combination demonstrated dramatic efficacy in three of the four models.

“In all tested PDXs, except LCF29, we have observed a significant, but variable, improvement of the antitumor efficacy of RAD001 + volasertib in comparison to each monotherapy (Figure 2A).”

To define this RAD001 + volasertib drug combination’s mechanism of action, the researchers conducted a pharmacodynamics (PD) study. The team then evaluated post-therapeutic proteins involved in the cell cycle, vascularization and carbonic anhydrase IX expression. These results were then validated using in vitro studies.

CONCLUSION

“Our determination of relevant Pi3K-based therapeutic combination(s) was not supported, by the presence of actual molecular abnormalities, nor by physician therapeutic practices, but by the identification of predictive markers of resistance to Pi3K-based monotherapies.”

In summary, the researchers conclude that their study demonstrates that inhibiting both mTORC1 and PLK1 proteins induces synergistic antitumor activity in multiple models of NSCLC. In the discussion section of this paper, the authors detailed the divergent methodology they used to come to their conclusion.

“This methodology may promote more relevant clinical trials and avoid non-efficient combinations, inacceptable toxicities, and expensive and time-consuming studies.”

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

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Trending With Impact: Promising Non-Small Cell Lung Cancer Prodrug

August 26, 2021

Researchers examined the preclinical prodrug LP-184 and its efficacy in treating non-small cell lung cancers that lack actionable targets or resistance-related genes.

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Between 20 and 40% of adults with non-small cell lung cancer (NSCLC) eventually go on to develop brain metastases. Over 40% of patients with NSCLC have limited treatment options due to a lack of actionable therapeutic targets. Treatment for such patients has been limited to non-targeted chemotherapy—an approach which increases the risk of developing drug-resistance due to underlying resistance-associated mutations.

“Newer drugs that will be more potent and remain efficacious in NSCLC with such mutations could lead to better alternate or combinatorial therapies.”

Lantern Pharma (a pharmaceutical company developing targeted cancer therapies) created a new drug candidate and next generation member of the acylfulvene class of prodrugs, named LP-184. Researchers from Lantern Pharma and REPROCELL (a commercial contract research organization) conducted a study to test the anti-tumor activity of this preclinical compound in a variety of NSCLC cell lines. In 2021, Oncotarget published team’s pape, entitled, “The acylfulvene alkylating agent, LP-184, retains nanomolar potency in non-small cell lung cancer carrying otherwise therapy-refractory mutations.”

The Study

Despite LP-184’s highly-synthetic sounding name, the lead product in this acylfulvene prodrug (Illudins) is derived from, you guessed it, Jack-o-Lantern mushrooms.

“Acylfulvenes have been derived from cytotoxic agents called Illudins, isolated from Jack-o-Lantern mushroom (Omphalotus illudens), that retain and improve the cytotoxicity of parent Illudins for use as anticancer agents.”

The anti-tumor activity of this compound is based on activation through reductive mechanisms, mediated by enzymes such as Prostaglandin Reductase 1 (PTGR1). PTGR1 is known to be upregulated in some tumors, including in tumors with mutations in KEAP1. LP-184 sensitivity was investigated in NSCLC cell lines with individual or combined mutations in KEAP1, KRAS, TP53, and STK11.

“There is a high unmet need for effective therapies for NSCLC harboring mutations in these genes that have not only been considered undruggable till date but also are associated with loss of efficacy or resistance to multiple therapeutic strategies, at least in frontline regimens.”

The researchers tested LP-184 in vitro in 19 primary and metastatic NSCLC cell lines to determine the range of NSCLC settings that this compound might work best in. Clinical data analyses were also conducted by the researchers to predict tumor responsiveness to LP-184. In addition, the compound was examined in two mouse models of primary lung cancer. Mouse models were tested for sensitivity to LP-184 in both two- and three-dimensional culture systems.

“We sought to assess LP-184 activity in a panel of selected NSCLC adenocarcinoma cell lines, determine associations between genomic and transcriptomic profiles and responses of cell lines tested, and compare in vitro potency of LP-184 with that of approved chemotherapy agents.”

Conclusion

Among their many findings, the researchers demonstrated that LP-184 has high nanomolar potency in 11 of the 19 NSCLC cell lines tested—indicating broad NSCLC anti-tumor activity. In vivo, LP-184 showed efficacy in terms of tumor regression in one of the two mouse models.

“We propose further evaluation of LP-184 in multiple PTGR1 high NSCLC settings that may not necessarily be mutually exclusive, including in highly prevalent KEAP1 and KRAS mutant tumors (Figure 6), and in patients with lack of actionable targets or resistance-related genes with no effective therapy options available.”

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

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Trending with Impact: Machine Learning Used to Compare ALK Inhibitors

March 8, 2021

Researchers use a computer simulated modeling system to highlight the strengths and weaknesses of two ALK inhibitors.

Figure 2: Overview of brigatinib’s and alectinib’s mechanisms of action.

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Despite many therapeutic advances over the years, over half of patients with lung cancer die within one year of diagnosis. Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancer, and around 3–7% of patients with NSCLC present with a rearranged ALK gene (ALK+). This abnormality produces aberrant ALK protein cell signaling pathway activity and causes cancer cells to grow and metastasize. ALK+ NSCLC patients often develop drug resistance to available ALK inhibitor drugs.

“Consequently, it is of the upmost importance to adequately use the currently available treatments in the correct order to maximize the life span of NSCLC patients.”

In 2021, researchers from Spain conducted a study published in Oncotarget, titled: “Head to head evaluation of second generation ALK inhibitors brigatinib and alectinib as first-line treatment for ALK+ NSCLC using an in silico systems biology-based approach.” This trending paper was authored by researchers practicing at the Hospital Germans Trias i Pujol, Takeda Farmacéutica España, Anaxomics Biotech, and Universitat Pompeu Fabra.

The Study

The researchers first began their study by characterizing the pathophysiology of ALK+ NSCLC after completing a detailed review of review papers published in PubMed between 2013 and 2018.

“To carefully characterize the pathophysiology of ALK+ NSCLC, we conducted an extensive and detailed full-length review of relevant review articles over the last 5 years in the PubMed database (from December 3rd 2013 to December 3rd 2018)[…]”

Next, to compare the strengths and weaknesses of two second generation ALK inhibitor drugs, brigatinib and alectinib, the researchers used a computer simulated modeling system—in silico. They explain that an in silico method of study can be highly useful when analyzing drug characteristics and predicting the biochemical characteristics and drug mechanisms of action.

“Overall, these systems can be employed for the exploration of anticancer drug mechanisms of action and their efficacy in specific patient profiles.”

The in silico system they used is called a Therapeutic Performance Mapping System (TPMS) and is based on artificial intelligence and pattern recognition models. This TPMS system was “trained” by the researchers in this study and given up-to-date biological and clinical data to input into its configuration. The mathematical models used to obtain the ALK inhibitors’ mechanisms of action were generated following the same methodology as described in this study.

“This methodology integrates available biological, pharmacological and medical information to generate mathematical models that simulate the mechanisms of action of drugs in a pathophysiological human context (Figure 4).”

To detect and explain the biological relationships that occur, the team used two distinct modeling methods: artificial neural networks and sampling-based methods. They applied Sobol sensibility analysis over the TPMS mathematical models in order to account for the impact of any noise affecting the final mechanisms of action. The researchers also performed drug-(patho)physiology motive relation finding and evaluated the impact of potential resistances and drug interferences over the mechanisms of action.

Results & Conclusion

“According to the current knowledge and the data herein presented, brigatinib might be more prone to present relevant metabolic and mechanistic interactions with other drugs than alectinib, which might be a safer option in poly-treated patients.”

“Brigatinib appears to have a wider mechanism of action, presenting targets that potentially act more strongly in most of the ALK+ NSCLC pathophysiological pathways, including invasiveness to the CNS [central nervous system].”

“On the other side, alectinib-induced RET inhibition might contribute to reducing the tumour immune evasion mechanisms.”

The researchers found that both drugs are known to be well-tolerated and show similar efficacy for the treatment of ALK+ NSCLC in a first-line setting. However, they explain that the differences in their characteristics shown in this study might allow for administration in more targeted patient populations that might see benefits from either brigatinib or alectinib. This deeper classification may also help when considering potential safety concerns in specific patient subpopulations.

“Future clinical studies will be needed to confirm these findings. The used approach can be applied for the evaluation of other next-generation ALKi, even if not yet approved, or exploring other questions, such as optimal treatment sequence.”

Click here to read the full scientific study, published in Oncotarget.

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