Tagged: Cancer Research

Triple Combination Treatment Overcomes Colorectal Cancer Resistance

December 14, 2023

In a new study, researchers aimed to elucidate the role of cancer stemness in the resistance of colorectal cancer cells to targeted therapies.

Triple Combination Treatment Overcomes Colorectal Cancer Resistance

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Colorectal cancer is the third most diagnosed cancer and the second leading cause of cancer-related deaths worldwide. It often starts in the colon or rectum with small, noncancerous clumps of cells called polyps, which can develop into cancer over time. Risk factors for colorectal cancer include age, family history, inflammatory bowel diseases, diet, smoking, and physical activity.

The development and progression of colorectal cancer are driven by the aberrant activation of multiple signaling pathways, such as EGFR (epidermal growth factor receptor), RAS-RAF, and PTEN-PI3K. Among these pathways, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathways are particularly important, as they are frequently mutated in colorectal cancer. Therapeutic targeting of these pathways has shown promise in suppressing tumor growth. However, cancer cells often develop resistance to targeted therapies, leading to treatment failure and disease progression.

In a new study, researchers Astha Lamichhane, Gary D. Luker, Seema Agarwal, and Hossein Tavana from The University of Akron, University of Michigan and Georgetown University aimed to elucidate the role of cancer stemness in the resistance of colorectal cancer cells to targeted therapies. Their research paper was published in Oncotarget on October 4, 2023, entitled, “Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells.”

The Study

One of the major mechanisms of drug resistance in cancer is the gain of stemness in cancer cells under drug pressure. Cancer stem cells (CSCs) are a small subpopulation of cells within a tumor with the ability to self-renew and differentiate into various cell types that constitute the tumor. CSCs are thought to be responsible for tumor initiation, progression, and resistance to therapy. Therefore, identifying approaches to target CSCs is crucial for improving treatment outcomes in colorectal cancer patients.

In the current study, the researchers developed spheroid cultures of patient-derived BRAFmut and KRASmut tumor cells and studied the resistance mechanisms to inhibition of the MAPK pathway. The researchers found that treatment with MAPK pathway inhibitors enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated the PI3K/Akt pathway in cancer cells. These findings suggest that the development of drug resistance in colorectal cancer is associated with the acquisition of a stem cell-like phenotype.

To overcome drug resistance mediated by cancer stemness, the researchers examined various combination treatments to block these activities. They found that a triple combination treatment targeting BRAF, EGFR, and MEK significantly reduced stemness and the activities of oncogenic signaling pathways in colorectal cancer cells. This triple combination treatment has shown promise in clinical trials, with response rates of 21% and 32% in patients with BRAFmut colorectal cancer. The researchers demonstrated that this combination treatment effectively suppressed the growth, stemness, and activities of several oncogenic signaling pathways in cancer cells.

“Our finding supports the hypothesis that CSCs confer drug resistance and suppressing stemness is a viable approach in BRAFmut colorectal cancer.”

Conclusion

Altogether, the researchers found that inhibiting BRAF, EGFR, and MEK in combination shows promise in suppressing cancer stemness and overcoming drug resistance in colorectal cancer cells. This approach targets the underlying mechanisms of resistance, providing a potential strategy for improving treatment outcomes in patients with colorectal cancer. Further research and clinical trials are needed to validate the efficacy and safety of this triple combination therapy.

“In conclusion, this study presented a model of cyclic drug treatment and recovery of patient-derived tumor spheroids and established that single-agent MEK inhibition of colorectal cancer cells lead to adaptive resistance of cancer cells through gain of stemness. A triple combination treatment used in a clinical trial of colorectal cancer patients effectively blocked growth, stemness, and activities of several oncogenic signaling pathways in cancer cells. Our approach to identify mechanisms of drug resistance of patient-derived cancer cells to targeted therapies and develop effective treatments is promising toward cancer precision medicine.”

Click here to read the full research paper 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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Can Mechanisms of Hair Loss Shed Light on Cancer and Aging?

November 29, 2023

In a 2023 study, researchers investigated hair loss and their findings may lead to a better understanding of tissue homeostasis, initiation of cancer and the aging process.

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Hair follicles are dynamic structures that undergo cyclic phases of growth, regression and quiescence. The growth phase, known as anagen, lasts for several years, followed by a short regression phase called catagen. During catagen, most cells within the follicle undergo programmed cell death, but a small population of stem cells remains viable to replenish the follicle during the subsequent growth phase. Understanding the mechanisms involved in hair follicle regression is not only important for elucidating normal tissue homeostasis but also for studying pathological conditions such as cancer and aging.

In a recent study, researchers Bradley D. Keister, Kailin R. Mesa and Krastan B. Blagoev from the National Science Foundation, The Jane Coffin Childs Memorial Fund for Medical Research, Yale School of Medicine, Johns Hopkins University, Bulgarian Academy of Sciences, and Sorbonne Université shed light on the role of apoptotic cells in hair follicle regression and cell death. Their research paper was published in Oncotarget on October 19, 2023, entitled, “Apoptotic cells may drive cell death in hair follicles during their regression cycle.”

“Here, we use a quantitative analysis of the length of hair follicles during their regression cycle.”

The Role of Apoptotic Cells in Hair Follicle Regression

In this study, researchers suggest that apoptotic cells play a crucial role in driving cell death during hair follicle regression. Intravital microscopy in live mice revealed that the elimination of epithelial cells involves supra-basal cell differentiation and basal cell apoptosis, which are influenced by the synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. The study also demonstrated that the basal epithelial cells are not internally committed to death, and the mesenchymal dermal papilla (DP) is essential in inducing apoptosis.

While the exact mechanism leading to the propagation of apoptosis towards the regenerative stem cell population remains unclear, the researchers proposed a quantitative analysis of the length of hair follicles during their regression cycle. The data obtained from this analysis suggested a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. Interestingly, the study found that apoptosis slows down as it approaches the stem cells at the end of the follicle, indicating the presence of a pro-survival signal released by these stem cells.

“In this paper we introduced a mathematical model of the hair follicle regression cycle that postulates that the regression is initiated by the dermal papilla, but that this signal affects only the cells adjacent to it.”

Hair Follicle Regression & Stem Cell Niches

To understand the dynamics of hair follicle regression, it is essential to consider the concept of stem cell niches. Adult stem cells, along with their supporting cells, form these niches, which maintain the functionality of renewable tissues in various organs. Stem cell niches have been identified in organs such as the colon, breast, skin, hair follicles, and bone marrow. Each organ has a distinct stem cell niche architecture, which can influence the rate of aging and susceptibility to cancer.

The study by Keister et al. highlights the importance of stem cell niches in hair follicle regression. The mesenchymal DP cells, located at the bottom of the follicle, were implicated in the initiation of regression through the release of a pro-apoptotic signal, possibly associated with TGF-β. While the DP cells are necessary for the initiation of regression, they are not required for the completion of the regression phase. This suggests that other mechanisms, in addition to the DP signal, contribute to the observed apoptotic propagation.

Quantitative Analysis of Hair Follicle Regression

The team conducted a quantitative analysis of hair follicle length during catagen to gain insights into the dynamics of regression. The study measured the length of hair follicles at two time points separated by 12 hours using intravital microscopy. The data revealed that shorter hair follicles regress at a slower rate compared to longer follicles. This observation suggests that the apoptotic propagation slows down as the dying cells approach the regenerative stem cell pool.

To explain the observed data, the researchers proposed a quantitative model in which apoptotic cells release a local signal that primes neighboring cells for apoptosis. Simultaneously, the stem cells release a pro-survival signal, creating a spatial gradient. This model is consistent with the experimentally measured distribution of follicle lengths and the deceleration of hair follicle regression. The simulations of the model demonstrated that the propagation of apoptosis along the follicle becomes slower and eventually stops when it reaches the stem cells.

The Power Law Distribution of Follicle Lengths

In addition to the quantitative analysis, the researchers investigated the distribution of follicle lengths during catagen. They found that the data obtained from the experiments were consistent with a power law distribution. (Note: The power law refers to the relationship between two quantities, stating that a relative change in one leads to a relative change in the other.) While the power law distribution was observed in the model, it is important to note that the biological lengths of the follicles make it challenging to have high confidence in this distribution. However, the model generated a power law probability distribution function, providing further support for its validity.

Implications & Future Directions

This research paper presents a comprehensive understanding of the role of apoptotic cells in hair follicle regression. The proposed model, which involves the interplay between apoptotic cells and stem cells, provides insights into the dynamics of regression and the maintenance of stem cell niches. Further research is needed to validate the model and explore the potential application to other stem cell niches in different organs.

The findings of this study have implications for the understanding of tissue homeostasis, initiation of cancer and the aging process. By unraveling the mechanisms behind hair follicle regression, researchers can gain valuable insights into the regulation of cell death and renewal in various tissues. This knowledge can potentially lead to advancements in regenerative medicine and the development of targeted therapies for conditions related to abnormal cell death and tissue regeneration.

“In conclusion, hair follicle regression may be governed by cell-cell induced programmed cell death, which slows down as the stem cell compartment is approached and does not affect the stem cell compartment from which the growth phase is initiated. […]. The generalization of the model to different geometries and topologies of different stem cell niches, as well as to the details of their stem cell renewal kinetics can address problems related [to] disease states like cancer and aging.”

Click here to read the full research paper in Oncotarget.

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Immunotherapy Response in Primary vs Metastatic Pancreatic Cancer

November 16, 2023

In this editorial, researchers delve into the immunotherapeutic challenges posed by the tumor microenvironment and liver metastasis in pancreatic cancer.

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Pancreatic ductal adenocarcinoma (PDA), a common type of pancreatic cancer, has proven to be largely resistant to immunotherapy, a treatment that uses the body’s immune system to fight cancer. Despite numerous successful pre-clinical trials using sophisticated PDA mouse models, clinical trials have failed to show a significant improvement in survival.

In a recent editorial, researchers Brian Diskin, Sarah Schwartz and George Miller from Trinity Health of New England shed light on the complex interplay between the immune system and pancreatic cancer. Their paper was published in Oncotarget on April 24, 2023, and entitled, “The critical immune basis for differential responses to immunotherapy in primary versus metastatic pancreatic cancer.”

Tumor Microenvironment and Liver Metastasis: Challenges in Pancreatic Cancer

The authors attribute PDA immunotherapy resistance to the unique characteristics of the tumor microenvironment (TME). The TME is often hypoxic and fibrotic, making it inaccessible to immune cells. Furthermore, the immune cells that do infiltrate the TME often have tolerogenic features, meaning they are more likely to tolerate the presence of cancer cells rather than attack them.

PDA most commonly metastasizes to the liver, an organ known for its immune tolerance. The liver is home to a diverse array of innate immune populations, including NK cells, Kupfer cells, NKT cells, and double negative T cells. Despite this, the liver is the most common location for metastasis from gastrointestinal cancers.

“It is an unfortunate fact that all failed clinical trials assessing immunotherapeutic efficacy were conducted in metastatic PDA, whereas basic preclinical investigations are usually performed in primary PDA using genetically engineered mouse models. We postulated that this dichotomy may explain the gap between preclinical promise and ultimate clinical failure.”

Divergent Responses to Immunotherapy: Primary vs. Metastatic

“The potentially divergent responses to immunotherapy in the respective environments of primary versus metastatic PDA within the same host has not been well-studied.”

The authors highlight the lack of research into the potentially divergent responses to immunotherapy in primary versus metastatic PDA. They argue that this gap in knowledge may explain the discrepancy between the promising results of pre-clinical trials and the disappointing outcomes of clinical trials.

In their research, they discovered that the TMEs of primary PDA and liver metastases differ significantly, and this difference plays a critical role in the site-specific response to immunotherapy. They found that liver metastases are uniquely resistant to immunotherapies, in stark contrast to the immunotherapeutic responsiveness of primary PDA.

“We discovered that the respective TMEs of primary PDA and liver metastases differ markedly and this fact plays a critical role in dictating site-specific PDA response to immunotherapy [6].”

The Role of B Cells

The researchers identified B cells as a key player in this differential response. They found that B cells constituted approximately 25% of the tumor-infiltrating lymphocytes in metastatic PDA liver deposits, compared to approximately 10% in primary PDA. They also discovered a novel population of CD24+CD44–CD40– B cells in the metastatic liver, which is recruited to the metastatic milieu by Muc1hiIL18hi tumor cells.

“[…] by targeting B cells or blocking CD200/BTLA, we demonstrated enhanced macrophage and T-cell immunogenicity, which enabled immunotherapeutic efficacy of liver metastases.”

However, the authors note that primary PDA sites lack this b-cell population. Instead, they are characterized by macrophages and effector T cells that have a higher ability to provoke an immune response. This makes their immunotherapeutic responsiveness far more robust than metastatic liver PDA.

Conclusion

This research underscores the importance of understanding the immune basis of differential responses to immunotherapy in primary versus metastatic pancreatic cancer. It highlights the need for further research into the role of the TME and immune cells like B cells in the response to immunotherapy. Such insights could pave the way for more effective treatments for this challenging disease.

“[…] our data suggest that models of primary PDA are poor surrogates for evaluating immunity or treatment response in advanced disease.”

Click here to read the full editorial paper in Oncotarget.

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p53’s Protective Role in Extrahepatic Biliary Precancerous Lesions

November 2, 2023

In this editorial, researchers from Japan discuss their recent study investigating the role of p53 in preventing the development of extrahepatic biliary cancer.

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Extrahepatic biliary cancer is a specific type of biliary cancer that occurs outside the liver. It is considered rare, quite serious and often symptomless until later stages. The average age at diagnosis is 72. Extrahepatic biliary cancer typically involves the bile ducts, which carry bile from the liver and gallbladder to the small intestine. It can also involve the gallbladder, which plays a role in the digestion of fats by storing, concentrating and releasing bile as needed.

One of the main genetic factors that contribute to biliary cancer is the mutation of Kras, a gene that regulates cell growth and division. Mutated Kras can cause cells to grow uncontrollably and form tumors. Another important genetic factor is the mutation of p53, a gene that normally acts as a guardian of the genome and triggers cell death or repair when DNA damage occurs. Mutated p53 can impair this function and allow cells to survive and accumulate more mutations.

“[…] the exact role of p53 in the development of extrahepatic biliary cancer remains elusive.”

In a new editorial paper, researchers Munemasa Nagao, Kenta Mizukoshi, Shinnosuke Nakayama, Mio Namikawa, Yukiko Hiramatsu, Takahisa Maruno, Yuki Nakanishi, Tatsuaki Tsuruyama, Akihisa Fukuda, and Hiroshi Seno from Kyoto University Graduate School of Medicine discussed their recent study exploring the role of p53 in preventing the development of extrahepatic biliary cancer. On March 31, 2023, their editorial was published in Oncotarget, entitled, “p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras.”

The Editorial

The authors of the editorial discuss their 2022 study using a mouse model to investigate how Kras and p53 mutations interact in the development of extrahepatic biliary cancer. They found that mice with Kras activation and p53 inactivation developed lesions resembling human biliary neoplasms in the bile duct and gallbladder. These lesions are considered to be precursors of invasive biliary cancer.

“In this study, we found that simultaneous activation of Kras and inactivation of p53 induces biliary neoplasms that resemble human biliary intraepithelial neoplasia in the extrahepatic bile duct and intracholecystic papillary tubular neoplasm in the gall bladder in mice.”

However, they also found that p53 inactivation was not enough for the progression of these lesions into invasive cancer in the presence of oncogenic Kras within the observation period. This was also true when they added another genetic alteration, namely the activation of the Wnt signaling pathway, which is known to promote tumorigenesis in various cancers.

Therefore, they concluded that p53 has a protective role against the formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras. They suggested that additional genetic or environmental factors may be required for the malignant transformation of these lesions into invasive cancer.

Conclusions

The study the authors described in their recent editorial paper provides new insights into the molecular mechanisms underlying extrahepatic biliary cancer and highlights the importance of p53 as a barrier against tumorigenesis. It also raises questions about what other factors may contribute to biliary cancer progression and how they can be targeted for prevention or treatment. This work received support from a number of institutions, including Grants-in-Aid KAKENHI, the Japan Agency for Medical Research and Development, the Princess Takamatsu Cancer Research Fund, the Mochida Foundation, the Mitsubishi Foundation, the Uehara Foundation, the Naito Foundation, the Kobayashi Foundation, the Simizu Foundation, the Japan Foundation for Applied Enzymology, the SGH Foundation, the Kanae Foundation, Bristol Myers Squibb, the Ichiro Kanehara Foundation, the Takeda Science Foundation, and the Takeda Foundation.

“In conclusion, p53 protects against formation of extrahepatic biliary precancerous lesions in the context of oncogenic Kras in mice, however, inactivation of p53 is not sufficient for the progression into invasive cancer in the extrahepatic biliary system.”

Click here to read the full editorial paper in Oncotarget.

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How a Metabolic Enzyme Can Trigger Cell Death in Liver Cancer Cells

October 19, 2023

In a new editorial paper, researchers highlight the role of GLS2 in regulating ferroptosis in hepatocellular carcinoma.

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Hepatocellular carcinoma (HCC) is the most common type of liver cancer. It is particularly challenging to treat because HCC is often diagnosed in late stage and resistant to chemotherapy and radiation. However, advancements in targeted therapies and immunotherapies have opened new avenues for the treatment of this aggressive disease.

In a new editorial paper, researchers Sawako Suzuki, Divya Venkatesh, Tomoaki Tanaka, and Carol Prives from Columbia University highlight the role of a metabolic enzyme known as glutamine synthase 2 (GLS2) in regulating ferroptosis in HCC. Ferroptosis is a form of cell death that involves iron-dependent accumulation of lipid peroxides. On October 19, 2023, their editorial was published in Oncotarget, entitled, “GLS2 shapes ferroptosis in hepatocellular carcinoma.”

GLS2 Promotes Ferroptosis in HCC

GLS2 is a key enzyme that catalyzes the conversion of glutamine to glutamate, a precursor of alpha-ketoglutarate (αKG), a molecule that participates in several metabolic pathways, such as the tricarboxylic acid (TCA) cycle, redox homeostasis and lipid and amino acid metabolism. GLS2 is also a transcriptional target of the tumor suppressor protein p53, which regulates its expression in response to cellular stress.

In this editorial, the researchers summarize findings from their recent study, which demonstrated that GLS2 is a bona fide tumor suppressor and a regulator of ferroptosis in HCC using mouse models and human cancer cells. The team showed that GLS2 deficiency leads to increased HCC tumorigenesis and resistance to ferroptosis, while GLS2 overexpression reduces tumor growth and sensitizes cancer cells to ferroptosis.

The mechanism by which GLS2 promotes ferroptosis involves its catalytic activity, which facilitates the production of αKG from glutamate. αKG then enhances lipid reactive oxygen species (ROS) generation by inhibiting the activity of glutathione peroxidase 4 (GPX4), an enzyme that protects cells from lipid peroxidation. Thus, GLS2 acts as a metabolic switch that favors ferroptosis by increasing lipid ROS levels.

“Our work has now provided evidence that GLS2 is mainly localized in mitochondria and induces ferroptosis through α-ketoglutarate (αKG), and this occurs specifically under conditions where the levels of GSH [glutathione] or of glutathione peroxidase 4 (GPX4) are suppressed by ferroptosis inducers [7].”

Conclusions

The authors also provided evidence that GLS2-mediated regulation of ferroptosis has clinical relevance for human HCC. They found that GLS2 expression is frequently downregulated in human HCC samples and correlates with poor prognosis. Moreover, they showed that GLS2 expression is associated with sensitivity to erastin, a ferroptosis-inducing agent, in human HCC cell lines.

These results suggest that GLS2 is a potential therapeutic target for HCC and that its modulation could enhance the efficacy of ferroptosis-based therapies. The editorial paper concludes by discussing the challenges and opportunities for further research on the role of GLS2 and ferroptosis in liver disease.

“If indeed GLS2 can promote chemically-induced ferroptosis irrespective of the tissue type, then the drug regimen will need to be tailored such that the liver tissues adjacent to HCC are protected. Taking these concerns into consideration, we hope that our findings will inform future decisions regarding treatment of liver disease.”

Click here to read the full editorial paper in Oncotarget.

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Genetic Insights into Early Breast Cancer in Kazakhstan

October 5, 2023

In this new study, researchers aimed to determine the genetic predisposition to early breast cancer in women from Kazakhstan.

Genetic Insights into Early Breast Cancer in Kazakhstan

Breast cancer (BC) is one of the most common and deadly cancers worldwide, affecting millions of women every year. However, not all women share the same risk of developing breast cancer. There are many factors that influence this disease, including age, lifestyle, family history, and genetic makeup.

One of the most important aspects of breast cancer research is to identify the genetic factors that predispose some women to develop breast cancer at an early age, especially in different ethnic groups that may have unique genetic variants. This can help to improve the prevention, diagnosis and treatment of breast cancer, as well as to reduce the health disparities among different populations.

In a new study, researchers Gulnur Zhunussova, Nazgul Omarbayeva, Dilyara Kaidarova, Saltanat Abdikerim, Natalya Mit, Ilya Kisselev, Kanagat Yergali, Aigul Zhunussova, Tatyana Goncharova, Aliya Abdrakhmanova, and Leyla Djansugurova from the Institute of Genetics and Physiology, Kazakh Institute of Oncology and Radiology, Al-Farabi Kazakh National University, and Asfendiyarov Kazakh National Medical University aimed to determine the genetic predisposition to early breast cancer in women from Kazakhstan — a population that has not been well studied before. On October 4, 2023, their research paper was published in Oncotarget, entitled, “Determination of genetic predisposition to early breast cancer in women of Kazakh ethnicity.”

“Our study may reveal previously uncharacterized population-specific variants that may increase the risk of BC in the Kazakh population.”

The Study

The researchers enrolled 224 unrelated Kazakh women diagnosed with early onset breast cancer. All patients were treated at the Kazakh Institute of Oncology and Radiology from August 2017 to October 2019. Cohort characteristics reported that the median age of the women was 34.6 years old (ranging between 19 and 40 years), 15.6% were diagnosed under the age of 30 and 13.8% had breast cancer within their family history. The researchers utilized next-generation sequencing (NGS) to perform a comprehensive analysis of germline mutations and gene expression profiles using the MiSeq platform. They used a targeted panel of 94 cancer-associated genes, including a vast number of genes implicated in hereditary cancer syndromes and overall breast cancer predisposition.

“To our knowledge, this is the first study using NGS technology to study the genetic predisposition to early-onset BC women from Kazakhstan and assess their impact on the patients’ clinical outcomes.”

The NGS-based multigene panel testing allowed the researchers to identify recurrent, possible founder and novel PVs in Kazakh women with early-onset BC that were undetected in earlier studies. Among 57 patients (25.4%), 38 unique pathogenic variants (PVs) were identified in 13 different cancer-predisposing genes. Notably, 12 of the 38 PVs were recurrent, including specific variants in BRCA1 and BRCA2 genes, which may represent founder mutations in this population. BRCA1 carriers had a significantly higher likelihood of developing triple-negative breast cancer and having a family history of breast cancer compared to non-carriers. Six of the 38 variants were novel.

“We demonstrated the remarkable efficacy of an NGS-based panel to identify rare germline variants in early onset BC patients. These findings could contribute to the development of population-specific multigene panels for more rapid and cost-effective testing.”

Conclusions

The study provides valuable insights into the genetic predisposition of early breast cancer in women of Kazakh ethnicity. It also highlights the value of next generation sequencing technology and the importance of studying different ethnic groups to understand the diversity and complexity of breast cancer genetics. The authors suggest that broadening the scope of genetic testing for hereditary breast cancer from only BRCA genes to testing multiple genes at once could lead to better results. However, further studies are needed to validate the clinical utility of the panels used in this study. Nonetheless, these findings may aid in developing personalized risk assessment and management strategies for Kazakh women with early-onset breast cancer, as well as to inform future clinical trials and treatments.

“With this in mind, we will focus in the future on segregation analyses of family members and functional analyses to evaluate the inheritance pattern and pathogenicity of the identified recurrent and novel BC variants. Retrospective analyses of their possible association with progression-free, metastasis-free, and overall survival are also an exciting direction for future research. No less interesting would be the study of these variants regarding the chemosensitivity and efficacy of specific targeted therapies for their carriers.”

Click here to read the full research paper in Oncotarget.

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Targeting Fatty Acid Binding Proteins in Multiple Myeloma

September 21, 2023

In a recent editorial, researchers discuss targeting fatty acid binding proteins to fight multiple myeloma.

Targeting Fatty Acid Binding Proteins in Multiple Myeloma

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Multiple myeloma (MM) is a type of blood cancer that affects plasma cells, which are responsible for producing antibodies. MM is characterized by the accumulation of abnormal plasma cells in the bone marrow, leading to bone damage, kidney failure, anemia, and increased susceptibility to infections. MM is a heterogeneous disease with different subtypes and genetic mutations that affect the prognosis and response to treatment. Therefore, there is a need for new biomarkers and therapeutic targets that can improve the outcomes of MM patients.

One of the potential targets that has recently emerged is the fatty acid binding protein (FABP) family. FABPs are proteins that bind and transport fatty acids, which are essential for energy production, cell signaling and membrane synthesis. FABPs are expressed in various tissues and organs, and have different roles depending on their location and type. There are nine members of the FABP family, but FABP5 seems to be the most relevant for MM.

In a recent editorial paper, researchers Heather Fairfield and Michaela R. Reagan from Maine Health Institute for Research, University of Maine and Tufts University School of Medicine summarized previous findings from their 2023 study and the current evidence on the role of FABPs in MM. On June 19, 2023, their editorial was published in Oncotarget, entitled, “The hope for targeting fatty acid binding proteins in multiple myeloma.”

“The FABPs hold promise as new therapeutic targets in multiple myeloma (MM), as described by our laboratory, and supported by in silico analyses [2] and other data [3, 4].”

Editorial Summary

The authors found that FABP5 expression is higher in MM cells than in normal plasma cells, and that high FABP5 levels are associated with worse survival and progression in MM patients. They also show that FABP inhibitors can reduce MM cell growth, survival and proliferation by affecting various pathways and processes, such as:

The unfolded protein response and ER stress response, which are activated by the high protein production in MM cells
The reactive oxygen species (ROS) generation, which can cause oxidative damage and apoptosis
The MYC oncogene expression and activity, which is essential for MM cell survival and proliferation
The mitochondrial function and metabolism, which are altered in MM cells to favor fatty acid oxidation
The DNA methylation patterns, which can affect gene expression and epigenetic regulation
The immune cell infiltration and cytokine production in the bone marrow microenvironment, which can modulate the tumor-host interactions

The researchers also highlighted findings from other studies that support the importance of FABPs in MM. For example, Jia et al. found that FABP5 expression correlates with immune cell changes in the MM microenvironment. Liang et al. found that FABP4 expression is increased in MM patients and that FABP4 knockout or inhibition can improve survival and reduce tumor burden in mice models.

“We reported studies showing either decreased tumor burden or no effect of FABP inhibition in vivo, and thus further optimization of in vivo targeting of FABPs, FABP inhibitor design, or overcoming FABP inhibitor resistance in the bone marrow is still required before translation to the clinic can materialize [1].”

Conclusion

The authors conclude that FABPs are promising prognostic markers and therapeutic targets in MM, and that further research is needed to elucidate their mechanisms of action and to develop specific inhibitors. They also suggest that targeting both tumor cell-derived and microenvironment-derived FABPs may be more effective than targeting either one alone.

This editorial provides a concise overview of the current state of knowledge on FABPs in MM, and highlights the potential benefits of targeting them for MM treatment. It also raises some interesting questions for future research, such as:

How do FABPs interact with other metabolic pathways and regulators in MM cells?
How do FABPs affect the bone remodeling process and osteolytic lesions in MM?
How do FABPs influence the drug resistance and relapse in MM?
How do different types of FABPs cooperate or compete with each other in MM?
How can FABP inhibitors be combined with other therapies for optimal efficacy and safety?

“Still, we are hopeful that by targeting FABPs, or following the science to other related pathways, it will be possible to revolutionize the therapy regimes currently used for MM patients.”

Click here to read the full editorial in Oncotarget.

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Predicting Functions of Cancer-Associated Genetic Variants

September 7, 2023

In a new editorial, researchers from the University of Illinois at Urbana-Champaign discuss the value of using computational models to predict the functions of cancer-associated genetic variants.

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How can we understand the role of genetic variations in cancer development and treatment? This is one of the most challenging and important questions in modern biology and medicine. A new editorial paper, by researchers Jun S. Song and Mohith Manjunath from the University of Illinois at Urbana-Champaign, offers a novel discussion involving computational methods to address this question. On August 30, 2023, their editorial was published in Oncotarget, entitled, “Predicting the molecular functions of regulatory genetic variants associated with cancer.”

“To date, over 490,000 genotype-phenotype associations have been discovered through large-scale genome-wide association studies (GWAS) [1]; however, molecular functions of most of these discovered GWAS variants remain unknown.”

In this editorial, the authors review recent advances and challenges in identifying and characterizing the functional effects of genetic variants that affect gene regulation, such as enhancers, promoters, and transcription factors. These variants, also known as expression quantitative trait loci (eQTLs), can modulate the expression levels of genes and influence various cellular processes and phenotypes, including cancer susceptibility and response to therapy.

The authors propose a framework for predicting the molecular functions of eQTLs based on their genomic context, epigenetic marks, chromatin accessibility, and three-dimensional interactions. They also discuss how to integrate multiple types of data and methods to improve the accuracy and interpretability of the predictions. Furthermore, they highlight the potential applications and implications of their approach for cancer research and precision medicine.

“A promising approach to address these challenges is to integrate genomic, epigenomic, transcriptomic and machine learning methods to identify functional genetic variants and characterize their mode of action in regulating target genes.”

Use Case: MITF and MYC

Microphthalmia-associated transcription factor (MITF) and MYC are two proteins of significant interest in cancer research. Due to their roles in gene regulation and their implications in cancer development and progression, they have been distinguished as oncoproteins. MITF and MYC belong to the basic helix-loop-helix (bHLH)-Zip family of transcription factors (TFs) and have a penchant for hexamer E-box motifs. E-box motifs play a crucial role in regulating gene expression by serving as binding sites for TFs, which can activate or repress the transcription of nearby genes. MITF and MYC are active in melanocytes and possibly vie for shared binding sites.

In their recent study, the researchers aimed to investigate how MITF and MYC interact with each other and with the E-box motifs in the melanocyte genome. They hypothesized that MITF and MYC might have different preferences for E-box variants, which could affect their binding affinity and gene regulation. To test this hypothesis, they used chromatin immunoprecipitation followed by sequencing (ChIP-seq) to map the genome-wide binding sites of MITF and MYC in melanocytes. They also used RNA sequencing (RNA-seq) to measure the gene expression changes after knocking down MITF or MYC. By integrating these data sets, they were able to identify the E-box motifs that were enriched or depleted in the binding sites of MITF and MYC, as well as the genes that were differentially expressed after altering their levels.

The results showed that MITF and MYC had distinct preferences for E-box variants, with MITF favoring CACGTG and MYC favoring CACATG. These preferences were consistent with their roles in gene regulation, as MITF was more likely to activate genes involved in melanocyte differentiation and pigmentation, while MYC was more likely to activate genes involved in cell proliferation and metabolism. The researchers also found that MITF and MYC had overlapping binding sites in some regions of the genome, which suggested that they might compete or cooperate with each other depending on the local context. Furthermore, they discovered that some E-box motifs were associated with higher or lower gene expression regardless of the presence of MITF or MYC, which indicated that other factors might also influence the transcriptional outcome.

The study provided new insights into the molecular mechanisms of MITF and MYC in melanocyte biology and cancer. It also demonstrated the utility of computational models for predicting TF binding sites and gene expression based on sequence features. The researchers suggested that future studies could extend their approach to other TFs and cell types, as well as explore the functional consequences of MITF-MYC interactions in vivo.

Conclusion

This editorial paper is a timely and comprehensive overview of the current and future directions in the field of functional genomics of cancer-associated eQTLs. It provides valuable insights and guidance for researchers who are interested in exploring this important and rapidly evolving area. Read the full paper to learn more about how to predict the molecular functions of regulatory genetic variants associated with cancer.

“Effectively integrating these rich resources with GWAS results will continue to help prioritize causative inherited genetic variants and improve our molecular understanding of disease etiology, assisting the discovery of actionable genes to improve human health.”

Click here to read the full editorial in Oncotarget.

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Mikhail Blagosklonny / Oncotarget

Dr. Mikhail Blagosklonny on Rapamycin Longevity Series

September 7, 2023

Dr. Mikhail Blagosklonny joins “Master One Thing” host Krister Kauppi to discuss the impact of his rapamycin research and hyperfunciton theory of aging.

The world’s leading Rapamycin researcher, Dr. Mikhail Blagosklonny, has a long background in cancer research and one important discovery he made around 2000 was that Rapamycin slowed down senescent cancer cells in different ways. After that step-by-step, his interest in the longevity field increased and he developed the very interesting hyperfunction theory of aging.

He has made a huge contribution in moving the Rapamycin longevity field forward and his research papers have impacted many people. For example, the Rapamycin physician Alan Green who – thanks to these papers – took the decision in 2017 to start prescribing Rapamycin off label. Today, Alan Green has the biggest clinical experience in the area with more than 1,200 patients. A lot of other physicians have after that also taken these steps and one of those, for example, is physician Peter Attia.

Interview Table of Contents:

02:32 Current situation and mission
04:07 Why did Rapamycin not prevent his cancer?
06:33 He develops a new type of cancer treatment
08:32 Hyperfunction theory of age-related diseases
10:38 mTOR drives age-related diseases
13:00 Hyperfunction theory and the car analogy
17:20 Difference between new and old version of hyperfunction theory
19:58 Prediction based on hyperfunction theory
21:38 Rapamycin seems to work at any age
23:55 Rapamycin will not make you immortal
26:21 Rapamycin delays lung cancer in mice
27:44 Hyperfunction theory and hormesis
29:13 Rapamycin combination with fasting or calorie restriction
30:33 Rapamycin combination with Acarbose or low carb diet
31:40 Rapamycin combination with exercise
33:04 Exercise and longevity effect
36:10 mTOR sweet spot
38:44 Why do centenarians live a long life?
40:36 Theory of accumulation of molecular damage
44:04 Hyperfunction theory was initially rejected
47:47 Rapamycin research that is missing
51:44 Rapamycin and bacterial infection
53:30 Rapamycin side effect on longevity dose regime
55:50 Rapamycin and pseudo-diabetes
58:51 Rapamycin combination of Acarbose or low carb diet
1:00:09 Rapamycin and increase in lipids
1:02:19 mTOR, mTORC1 and mTORC2
1:05:22 Mikhail’s self-experimentation with Rapamycin
1:10:41 Rapamycin and traditional medical care
1:11:13 Rapamycin and unacceptable side effects
1:14:26 Rapamycin and combinations to avoid
1:16:55 Rapamycin and high protein intake
1:18:08 Best time to start taking Rapamycin
1:21:00 Does Rapamycin prevent cancer or not?
1:23:52 Autophagy is a double-edged sword
1:26:51 Important insight from his cancer
1:28:38 Rapamycin rebound effect
1:30:24 Difference between theory and practice
1:32:45 Mikhail’s cancer and cancer treatment
1:37:36 Rapamycin and danger

Dr. Blagosklonny’s Links:

Research publications – https://pubmed.ncbi.nlm.nih.gov/?term …
X/Twitter – https://twitter.com/Blagosklonny
Website – https://www.mikhailblagosklonny.com

Rapamycin resources:

Rapamycin.news – https://www.rapamycin.news
Rapamycin Facebook group – https://www.facebook.com/groups/rapam …
Rapamycin Reddit group – https://www.reddit.com/r/Rapamycin/

Disclaimer from host Krister Kauppi:

The podcast is for general information and educational purposes only and is not medical advice for you or others. The use of information and materials linked to the podcast is at the users own risk. Always consult your physician with anything you do regarding your health or medical condition.

Oncotarget

Whole-Genome Doubling and Aneuploidy in Human Cancer

August 10, 2023

In a new editorial paper, researchers from Tel Aviv University discuss a recent study exploring how whole-genome doubling shapes the aneuploidy landscape of human cancers.

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Whole-genome doubling (WGD) and aneuploidy are two common genomic alterations that occur in human cancers. WGD is a macro-evolutionary event that results in the duplication of the entire genome, while aneuploidy is a micro-evolutionary event that results in the gain or loss of individual chromosomes or chromosome arms. Both WGD and aneuploidy can have profound effects on cellular physiology, gene expression and genome stability, and are associated with tumor initiation, progression and drug resistance.

However, the relationship between WGD and aneuploidy is complex and context-dependent. In a new editorial paper, researchers Kavya Prasad and Uri Ben-David from Tel Aviv University discuss a recent study exploring how WGD shapes the aneuploidy landscape of human cancers. Their editorial was published in Oncotarget on April 26, 2023, and entitled, “A balancing act: how whole-genome doubling and aneuploidy interact in human cancer.”

“It is known that tumors that have undergone WGD are more permissive to aneuploidy, but whether WGD also affects aneuploidy patterns has remained an open question.”

The Study

The researchers analyzed 5,586 clinical tumor samples that had not undergone WGD (WGD-) and 3,435 tumors that had (WGD+) from The Cancer Genome Atlas (TCGA), across 22 tumor types. They found that WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, suggesting that WGD+ tumors are more tolerant to aneuploidy than WGD- tumors.

The genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, resulting in different co-occurrence and mutual exclusivity patterns. The proportion of whole-chromosome aneuploidy was significantly higher in WGD+ tumors than in WGD- tumors, indicating that different mechanisms of aneuploidy formation are dominant in WGD- and WGD+ tumors. The authors proposed that whole-chromosome missegregation is more prevalent in WGD+ tumors due to increased centrosome amplification and multipolar mitoses.

To validate their findings from the clinical tumor analysis, the authors used human cancer cell lines that reproduced the WGD/aneuploidy interactions observed in vivo. They also induced WGD in human colon cancer cell lines by treating them with a microtubule-stabilizing drug, and followed the evolution of aneuploidy in the isogenic WGD+/WGD- cells under standard or selective conditions. These experiments confirmed that WGD alters the aneuploidy landscape of human cancer cells, and revealed a causal link between WGD and altered aneuploidy patterns.

“We note that these experiments were not powered to assess the associations between specific aneuploidies, which remain to be experimentally validated in future studies.”

Conclusions & Future Studies

In their editorial, the researchers note that their study prompts questions about how different tetraploidization methods affect aneuploidy landscapes. They used cytokinesis failure for cell lines, but processes like cell fusion could impact aneuploidy differently. Further research should explore how selection pressures shape karyotype evolution, considering factors beyond tissue type. Analyzing intra-chromosomal arm-level vs. whole-chromosomal aneuploidies may identify cancer-driving chromosome arms. Overall, this study provides novel insights into how WGD and aneuploidy interact in human cancer, and how this interaction affects tumor evolution. The authors suggest that the interaction between WGD and aneuploidy is a major contributor to tumor heterogeneity, adaptation, and drug resistance, and that targeting this interaction could be a promising therapeutic strategy.

“In summary, our recent study shows that WGD contributes to aneuploidy formation in human tumors in both qualitative and quantitative ways. Hence, we propose that the WGD status of the tumor should be taken into account when examining the tumorigenic role of individual aneuploidies or aneuploidy patterns. In general, WGD should be considered in the study of aneuploidy landscapes in human cancers.”

Click here to read the full editorial in Oncotarget.

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