Category: Oncotarget

Genetic Alterations in Thyroid Cancer: Resistance to BRAFi and Anaplastic Transformation

February 8, 2024

In this new research perspective, researchers discuss the role of genetic alterations in resistance to BRAF inhibition and anaplastic transformation in thyroid cancer.

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Thyroid cancer is a complex disease with various subtypes and clinical presentations. While some cases can be successfully treated with standard therapy, others present challenges due to resistance to treatment and the development of aggressive forms of the disease. In a new research perspective, researchers Mark Lee and Luc GT Morris from New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center discuss the recent research that has shed light on the role of genetic alterations in mediating both resistance to BRAF inhibition and anaplastic transformation in thyroid cancer. On January 24, 2024, their paper was published in Oncotarget, entitled, “Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.”

“An improved understanding of the molecular basis of thyroid cancer has led to the development of new targeted agents.”

Understanding Thyroid Cancer and its Molecular Landscape

Thyroid cancer is generally characterized by well-differentiated histology and a relatively indolent course. However, a subset of patients presents with more advanced disease or dedifferentiated histologies that are less responsive to standard therapy. These dedifferentiated subtypes include anaplastic thyroid cancers (ATC) and poorly differentiated thyroid cancers (PDTC), which are thought to arise from a process of microevolution from papillary thyroid cancers (PTC).

The mitogen-activated protein kinase (MAPK) pathway plays a crucial role in regulating cell proliferation and differentiation. Mutations in this pathway, particularly in the BRAF gene (specifically the V600E mutation), have been identified in a significant proportion of thyroid cancers. The BRAF V600E mutation leads to constitutive activation of the MAPK pathway, resulting in dedifferentiation and tumor progression.

BRAF Inhibition as a Therapeutic Approach

Given the role of the BRAF V600E mutation in thyroid cancer, targeted agents that inhibit BRAF have been explored as potential treatments. Sorafenib and lenvatinib were the first agents approved for use in thyroid cancer but have shown limited overall survival benefits. More recent agents, such as vemurafenib and dabrafenib, specifically target the V600E mutant oncoprotein and have demonstrated promising results in early trials.

However, despite initial responses, the long-term efficacy of BRAF inhibitors is limited due to the emergence of resistance mechanisms. Multiple compensatory pathways and mutations have been observed in thyroid carcinoma cells that mediate bypass of BRAF blockade, leading to disease progression. These mechanisms can be primary, already present in the tumor, or secondary, acquired over the course of treatment.

Genetic Alterations Associated with Resistance to BRAF Inhibition

Recent studies have identified specific genetic alterations that are associated with resistance to BRAF inhibitors and anaplastic transformation in thyroid cancer. One such alteration is the presence of mutations in the PI3K/AKT/mTOR pathway, particularly in the PIK3CA gene. These mutations paradoxically hyperactivate the ERK pathway when BRAF is inhibited, leading to decreased response to therapy].

Other genetic alterations associated with resistance include mutations in the MAPK/ERK pathway (such as MET amplifications, NF2, NRAS, and RASA1), the SWI/SNF chromatin remodeling complex (ARID2 and PBRM1), and the JAK/STAT pathway (JAK1). These alterations have been observed in tumors that dedifferentiate after treatment with BRAF inhibitors, suggesting their involvement in both resistance and anaplastic transformation.

Mechanisms of Anaplastic Transformation in Thyroid Cancer

Anaplastic transformation, the transition from well-differentiated to dedifferentiated thyroid cancer, is a rare but aggressive form of the disease. The mechanisms underlying anaplastic transformation are not fully understood but likely involve genetic and molecular changes that drive the loss of cellular differentiation.

Ultrastructural analyses have shown that well-differentiated thyroid carcinomas transforming into anaplastic thyroid cancers undergo changes in cellular architecture, including the loss of tight junctions, desmosomes, and cellular polarity. Molecular alterations associated with anaplastic transformation include aneuploidy, increased copy number alterations, and mutations affecting genes such as p53, bcl-2, cyclin D1, β-catenin, Met, c-myc, Nm23, and Ras.

Overlapping Mechanisms of Resistance and Anaplastic Transformation

Recent research has revealed a significant overlap between the genetic alterations associated with resistance to BRAF inhibitors and the development of anaplastic thyroid cancer. Studies have shown that tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, including mutations in the PI3K/AKT/mTOR, MAPK/ERK, SWI/SNF chromatin remodeling complex, and JAK/STAT pathways.

These findings suggest that selective pressures exerted by BRAF inhibition can promote the outgrowth of subclones harboring these mutations, ultimately leading to anaplastic transformation. The complex and multifactorial nature of these compensatory mechanisms underscores the need for alternative treatment strategies to address resistance and improve long-term disease control.

Immune Microenvironment in Resistance and Anaplastic Transformation

The immune microenvironment of thyroid tumors has been a topic of active investigation, as it plays a crucial role in both tumor pathogenesis and drug resistance. While BRAF inhibitors are thought to increase anti-tumor immunity, they may also have competing effects, such as driving tumor infiltration by macrophages. Anaplastic thyroid cancer is associated with changes in the immune milieu, including increased infiltration by macrophages and fibroblasts.

The immunosuppressive microenvironment observed in resistance to BRAF inhibitors and anaplastic evolution suggests a potential role for combined targeted therapy with immunotherapy. Preclinical studies have shown that the combination of BRAF inhibitors with immune checkpoint inhibitors can enhance anti-tumor immune activity. Clinical trials evaluating the efficacy of combined BRAF blockade with immunomodulatory therapies are ongoing, with preliminary results showing promising anti-tumor effects.

Current Approaches and Future Directions

The current standard therapeutic approach for locally advanced, recurrent, metastatic, and dedifferentiated thyroid cancers involves surgical resection and adjuvant radioactive iodine therapy. However, in cases where surgery is not feasible or tumors are resistant to standard therapy, targeted agents have emerged as potential treatment options.

For patients with ATCs harboring the BRAF V600E mutation, neoadjuvant combination kinase inhibition with dabrafenib plus trametinib has shown promise . Other targeted agents, such as everolimus (MTOR inhibitor), crizotinib (MET inhibitor), and PI3K inhibitors, have demonstrated antitumor activity in preclinical and early clinical studies.

Combined BRAF blockade with immunotherapy is also being investigated as a potential treatment strategy. Early clinical trials have shown promising outcomes, with significant partial response rates and stable disease rates in advanced thyroid cancers. However, further studies with long-term follow-up are needed to evaluate the real-world effectiveness of these novel immunotherapies in combination with targeted therapy.

Conclusion

Genetic alterations play a crucial role in mediating both resistance to BRAF inhibition and anaplastic transformation in thyroid cancer. Understanding the mechanisms underlying these processes is essential for developing effective treatment strategies. Targeted therapies, such as BRAF inhibitors, have shown initial promise but are limited by the emergence of compensatory mechanisms.

The identification of specific genetic alterations associated with resistance and anaplastic transformation provides insights into potential therapeutic targets. Combined targeted therapy with immunomodulatory agents is being explored as a means to enhance anti-tumor immune activity and overcome resistance. Ongoing clinical trials will further elucidate the effectiveness of these novel treatment approaches and pave the way for personalized therapies for patients with thyroid cancer.

In conclusion, the study of genetic alterations in thyroid cancer has provided valuable insights into the development of resistance to targeted therapies and the progression to more aggressive forms of the disease. By understanding the underlying mechanisms and identifying potential therapeutic targets, researchers can work towards improved treatment strategies and better outcomes for patients with thyroid cancer.

“Dual-target therapies have been trialed but with continued limitations to long-term disease control. Thyroid tumor dedifferentiation and BRAF inhibitor resistance are also found to be associated with a transition to an immunosuppressed state. Early studies on combined targeted and immune-modulated therapy have demonstrated promising outcomes. Further clinical studies are needed to test real-world effectiveness of these novel immunotherapies with targeted therapy.”

Click here to read the full research perspective 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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New Drug May Boost Effectiveness of Glioblastoma Treatment

January 25, 2024

In a new study, researchers investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with standard therapy in multiple glioblastoma cell lines.

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Glioblastoma is a type of brain cancer that is very aggressive and difficult to treat. The current standard treatment involves surgery, radiation therapy, and chemotherapy with a drug called temozolomide (TMZ). However, many glioblastoma cells can resist the DNA-damaging effects of TMZ and radiation by activating a mechanism called the DNA damage response (DDR). This mechanism, while beneficial in normal cells, is detrimental to cancer therapy because it allows cancer cells to repair damage and continue to grow and divide. There is a need to counteract this mechanism in glioblastoma cancer cells.

In a new study, researchers Mathew Lozinski, Nikola A. Bowden, Moira C. Graves, Michael Fay, Bryan W. Day, Brett W. Stringer, and Paul A. Tooney from University of Newcastle, Hunter Medical Research Institute, GenesisCare, QIMR Berghofer Medical Research Institute, and Griffith University found that a drug called gartisertib may overcome this resistance by inhibiting a key protein involved in the DDR, called ataxia-telangiectasia and Rad3-Related protein (ATR). On January 16, 2024, the researchers published their new research paper in Oncotarget’s Volume 15, entitled, “ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines.”

“Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines.”

The Study

In this study, the team tested the effects of gartisertib alone and in combination with TMZ and radiation in 12 patient-derived glioblastoma cell lines. They found that gartisertib alone reduced the viability of glioblastoma cells, and that the sensitivity was associated with the frequency of DDR mutations and the expression of genes involved in the G2 phase of the cell cycle (the phase where cells prepare for division and check for DNA damage). The researchers also found that gartisertib enhanced the cell death induced by TMZ and radiation, and that the combination was more synergistic than TMZ and radiation alone.

Interestingly, gartisertib was more effective in glioblastoma cells that had unmethylated MGMT promoters and were resistant to TMZ and radiation. (MGMT is a gene that encodes an enzyme that can reverse the damage caused by TMZ, and its promoter is a region that controls its expression. Methylation is a chemical modification that can silence genes, so unmethylated MGMT promoters mean higher MGMT expression and more resistance to TMZ.) The researchers also analyzed the gene expression changes in glioblastoma cells treated with gartisertib, and found that the drug upregulated pathways related to the innate immune system. The researchers speculated that gartisertib may trigger an immune response against glioblastoma cells, which could enhance the anti-tumor effects of the drug.

“We showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment. MGMT promoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways.”

Conclusion

The study is the first to demonstrate the activity of gartisertib in patient-derived glioblastoma cell lines, and it provides evidence that ATR inhibition may be a promising strategy to improve the outcomes of glioblastoma patients. Gartisertib is a potent and selective inhibitor of ATR that has been tested in a phase 1 clinical trial for patients with advanced solid tumors. The researchers suggest that further studies are needed to evaluate the safety and efficacy of gartisertib in combination with TMZ and radiation in glioblastoma patients, and to explore the potential role of the immune system in mediating the anti-tumor effects of the drug.

“In conclusion, this study identifies gartisertib as a potent ATRi within patient-derived glioblastoma cell lines. […] Further investigation of the concept of ATR inhibition for treatment of brain tumours, especially in vivo with brain penetrant compounds, is needed to validate these findings. Lastly, ATR inhibition alters the gene expression of innate immune and inflammatory signalling pathways within glioblastoma cells, which requires additional validation and investigation as a strategy to provoke an immunomodulatory response.”

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How Osteopontin Stimulates Mitochondrial Biogenesis and Cancer Metastasis

January 11, 2024

In this new study, researchers investigated the role of Osteopontin splice variants in cancer metastasis.

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Mitochondrial biogenesis, the process of increasing the size and number of mitochondria within cells, plays a crucial role in cancer metastasis. Metastasizing cells exhibit a unique metabolism that differs from the well-known Warburg effect observed in primary tumors. While primary tumors primarily rely on glycolysis for energy production, metastatic cells rely on oxidative phosphorylation and ATP generation for short-term energy needs. However, over longer time frames, mitochondrial biogenesis becomes a prominent feature in the success of metastasis.

In a new study, researchers Gulimirerouzi Fnu and Georg F. Weber from the University of Cincinnati’s James L. Winkle College of Pharmacy investigate the connection between short-term oxidative metabolism and long-term mitochondrial biogenesis in cancer metastasis. They hypothesized that Osteopontin splice variants, specifically Osteopontin-c, stimulate an increase in mitochondrial size through the activation of specific signaling mechanisms. On December 1, 2023, their new research paper was published in Oncotarget, entitled, “Osteopontin induces mitochondrial biogenesis in deadherent cancer cells.”

“Over longer time frames, mitochondrial biogenesis becomes a pronounced feature and aids metastatic success. It has not been known whether or how these two phenomena are connected. We hypothesized that Osteopontin splice variants, which synergize to increase ATP levels in deadherent cells, also increase the mitochondrial mass via the same signaling mechanisms.”

The Role of Osteopontin Variants in Mitochondrial Biogenesis

Deadhesion, the process of detaching cancer cells from the extracellular matrix, is known to induce metabolic reprogramming and promote cancer cell survival in circulation. Osteopontin (OPN), a cytokine produced by cancer cells, has been implicated in tumor progression and the development of metastases. It mediates tumor cell survival and expansion under deadherent conditions, making it an ideal candidate for studying the mechanisms behind mitochondrial biogenesis. The authors of the research paper focused on two Osteopontin splice variants, Osteopontin-a and Osteopontin-c, and their effects on mitochondrial biogenesis.

Through their experiments with breast tumor cells, the authors found that both Osteopontin-a and Osteopontin-c contribute to mitochondrial biogenesis in deadherent cells. However, Osteopontin-c was more effective in stimulating an increase in mitochondrial size compared to Osteopontin-a. The authors also observed that the autocrine effects of Osteopontin variants are critical for the survival and anchorage-independence of disseminating malignant cells.

The Role of CD44v and SLC7A11 in Osteopontin Signaling

To further elucidate the mechanism behind Osteopontin-induced mitochondrial biogenesis, the authors investigated the receptors involved in Osteopontin signaling. They focused on CD44, a cell surface receptor known to interact with Osteopontin, and its variant CD44v. The authors found that Osteopontin-induced mitochondrial biogenesis is mediated via the binding of Osteopontin to CD44v.

Additionally, the authors discovered that the chloride-dependent cystine-glutamate transporter SLC7A11 plays a crucial role in Osteopontin signaling. The upregulation and co-ligation of SLC7A11, along with CD44v, leads to the activation of PGC-1, a known inducer of mitochondrial biogenesis. Surprisingly, the authors found that peroxide, an important intermediate in this signaling cascade, acts upstream of PGC-1 and is likely produced as a consequence of SLC7A11 recruitment and activation.

In Vivo Implications and Therapeutic Targets

To validate the relevance of their findings in clinical settings, the authors analyzed gene expression profiles in breast cancer metastases and metastases from other types of cancers. They identified the master regulator of mitochondrial biogenesis, PPARG, as well as its downstream effectors NRF1 and BACH1, to be upregulated in various metastases. These findings suggest that the Osteopontin-induced activation of PGC-1 and subsequent mitochondrial biogenesis may play a crucial role in cancer metastasis.

The authors also conducted in vivo experiments using mouse models. They observed that suppression of the biogenesis-inducing mechanisms led to a reduction in disseminated tumor mass. These findings not only confirm the functional connection between short-term oxidative metabolism and long-term mitochondrial biogenesis in cancer metastasis but also provide potential mechanisms and targets for treating cancer metastasis.

Conclusion

This study provides valuable insights into the role of Osteopontin splice variants in regulating mitochondrial biogenesis in metastatic cancer cells. The researchers demonstrated that Osteopontin-c stimulates an increase in mitochondrial size through the activation of specific signaling mechanisms involving CD44v and SLC7A11. These findings have significant implications for understanding the metabolic adaptations of metastatic cancer cells and suggest potential targets for therapeutic interventions. Further research is needed to fully elucidate the intricate signaling pathways involved in Osteopontin-induced mitochondrial biogenesis and to explore the clinical applications of these findings in cancer treatment.

“This study confirms a functional connection between the short-term oxidative metabolism and the longer-term mitochondrial biogenesis in cancer metastasis – both are induced by Osteopontin-c. The results imply possible mechanisms and targets for treating cancer metastasis.”

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Melatonin in Cancer Therapy: Lessons From 50 Years of Research

December 28, 2023

In a new research perspective, researchers discuss melatonin’s effects on cancer and the key importance of the timing of administration.

Melatonin in Cancer Therapy: Lessons From 50 Years of Research

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In the realm of cancer research, the potential of melatonin as an anti-cancer agent has garnered significant attention. Over the past 50 years, numerous studies have been conducted to investigate the effects of melatonin on tumor growth and development in mice. These studies have provided valuable insights into the complex relationship between melatonin and carcinogenesis.

In a new research perspective, researchers Vladimir N. Anisimov and Alexey G. Golubev from N.N. Petrov National Medical Research Center of Oncology wrote about the history of studies of melatonin effects on cancer in mice. Their paper was published in Oncotarget on December 12, 2023, entitled, “Melatonin and carcinogenesis in mice: the 50th anniversary of relationships.”

Early Discoveries and Controversies

In 1973, Vladimir N. Anisimov and his coauthors made a groundbreaking discovery by demonstrating the inhibitory effect of melatonin on transplantable mammary tumors in mice. This pivotal study laid the foundation for subsequent investigations into the potential anti-cancer properties of melatonin. However, early studies encountered controversies regarding the consistency of melatonin’s effects on in vivo cancer models. The lack of consistency in these studies prompted further exploration of the factors influencing melatonin’s efficacy.

Importance of Timing in Melatonin Administration

One of the crucial findings in melatonin research is the significant impact of timing in melatonin administration. Bartsch and Bartsch demonstrated that the effects of melatonin on cancer in mice depend on the time of treatment. The administration of melatonin in the morning stimulated tumor growth, while late afternoon administration inhibited it. This observation highlighted the importance of considering animal conditions and the systemic effects of melatonin when evaluating its anti-cancer properties. These systemic effects may not be evident in cell cultures or ex vivo explants.

Murine Models for Melatonin and Cancer Studies

Murine models have played a pivotal role in elucidating the effects of melatonin on various types of cancer. These models have provided valuable insights into the potential utility of melatonin in oncology. Some of the notable murine models include mice grafted with murine tumors, chemically induced tumors, spontaneous carcinogenesis in mice, transgenic HER2/neu oncogene-bearing mice, and nude mice grafted with human prostate tumors. These models have allowed researchers to evaluate not only the effects of melatonin on cancer development but also its impact on the efficacy and side effects of anticancer therapies.

Melatonin’s Effects on Spontaneous Tumor Incidence

One intriguing finding in murine studies is the effect of melatonin on spontaneous tumor incidence. Anisimov et al. showed that lifelong treatment of mice with melatonin decreased the incidence of spontaneous tumors, particularly mammary carcinomas, but only at a low concentration of melatonin in drinking water. Interestingly, this effect was not observed at a high melatonin concentration. These findings suggest that the dose of melatonin may play a crucial role in its anti-cancer effects.

Melatonin’s Role in Potentiating Cytotoxic Therapy

Another area of interest in melatonin research is its potential to enhance the efficacy of cytotoxic therapy against tumors. Panchenko et al. demonstrated that the timing of melatonin administration relative to cytotoxic drug administration significantly influenced its potentiating effect on cytotoxic therapy in HER2/neu transgenic mice. This finding highlights the importance of optimizing the timing of melatonin administration in combination with other cancer treatments.

Melatonin’s Protective Effects on Side Effects

Beyond its direct anti-cancer effects, melatonin has shown promise in alleviating the side effects of cytotoxic drugs and radiation therapy. Several murine models have demonstrated the ability of melatonin to mitigate the side effects associated with these treatments. For example, melatonin was shown to alleviate the depression syndrome in mice treated with the alkylating agent temozolomide used in brain cancer therapy. Additionally, melatonin has been found to protect against ovarian follicle depletion caused by cisplatin, a commonly used chemotherapy drug. These findings suggest that melatonin may have a broader role in cancer treatment by reducing the adverse effects of traditional therapies.

Melatonin’s Effects on Metastasis and Epithelial-Mesenchymal Transition

Metastasis is a significant challenge in cancer treatment, and melatonin has shown promise in inhibiting metastatic spread. In nude mice grafted with human gastric cancer, melatonin was found to suppress lung metastases development by inhibiting the epithelial-to-mesenchymal transition (EMT). The inhibition of EMT by melatonin has also been observed in other murine models, highlighting its potential as an anti-metastatic agent. Given the crucial role of EMT in primary cancer and metastasis development, these findings have significant implications for oncology research.

Melatonin and Inflammation

Chronic inflammation is increasingly recognized as a contributing factor in cancer development and progression. Melatonin has been found to modulate inflammatory processes in murine models. In a murine model of low-grade inflammation, melatonin inhibited EMT), suggesting a potential role in suppressing cancer-related inflammation. While the direct anti-inflammatory effects of melatonin require further investigation, these findings shed light on the multifaceted mechanisms through which melatonin may exert its anti-cancer effects.

Clinical Applications and Promising Results

The employment of melatonin in clinical settings beyond its established fields does not require licensing, making it more readily accessible for testing novel applications in cancer treatment. Promising clinical results have already been reported, such as increased overall survival in prostate cancer patients with poor prognosis after combined hormone radiation treatment. These findings highlight the potential translational impact of murine studies and underscore the importance of continued research to fully understand the clinical implications of melatonin in cancer therapy.

Conclusion

Over the past 50 years, murine models have provided valuable insights into the relationship between melatonin and carcinogenesis. These studies have shed light on the importance of timing in melatonin administration, its effects on tumor incidence and metastasis, as well as its role in potentiating cytotoxic therapy and mitigating side effects. While the precise mechanisms underlying melatonin’s anti-cancer effects require further exploration, the promising results observed in both preclinical and clinical studies warrant continued investigation. As researchers continue to unravel the complexities of melatonin’s interactions with cancer, new opportunities for therapeutic interventions may emerge, offering hope for improved cancer treatment outcomes.

“The […] main lesson being that the systemic in vivo effects of melatonin on animals may overwhelm the in vitro effects found using tissue explants or cell cultures. In particular, the timing of melatonin administration is of crucial importance for using the drug, which is freely available over [the] counter and thus needs no licensing for its applications in oncology.”

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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.”

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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.”

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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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Oncotarget

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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Oncotarget

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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Oncotarget

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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