Tagged: Cancer Research

Trending With Impact: Adjunct Virotherapy Fights Multiple Myeloma

March 17, 2022

Researchers investigated using oncolytic viruses to treat multiple myeloma—alone and in a combination approach.

3D red blood cells in vein — 3D red blood cells

The Trending With Impact series highlights Oncotarget publications attracting higher visibility among readers around the world online, in the news, and on social media—beyond normal readership levels. Look for future science news about the latest trending publications here, and at Oncotarget.com.

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Multiple myeloma (MM) is a currently incurable cancer of blood plasma cells. Autologous stem cell transplantation (ASCT) has had efficacious results among eligible patients. However, even after ASCT, a significant number of patients continue to relapse and become resistant to current standard therapies.

A promising new method to treat blood cancers is a form of immunotherapy called virotherapy. Oncolytic viruses are uniquely capable of being reprogrammed to selectively infect and kill various cancer cells without infecting or damaging normal cells in host organisms, including mice and humans. Researchers from Arizona State University, Emory University and the Mayo Clinic (in Scottsdale, Arizona) had previously experimented with using the oncolytic myxoma virus (MYXV) to treat MM. In nature, MYXV only affects rabbits and is innocuous in mice and humans. They found that MYXVs delivered through stem cell transplantation can eliminate some residual MM cells in the Balb/c mouse model.

“Recently, we reported that ex vivo virotherapy with oncolytic myxoma virus (MYXV) improved MM-free survival in an autologous-transplant Balb/c mouse model.”

However, the researchers found that Balb/c mice may not be ideal models for MM. They observed that the behavior of MM in Balb/c mice did not quite reflect the development, clinical manifestation and localization of MM observed in human patients. Therefore, the team conducted a new study of MYXVs in the Vk*MYC transplantable C57BL/6 mouse MM model. Their trending research paper was published in Oncotarget on March 3, 2022, and entitled, “Transplantation of autologous bone marrow pre-loaded ex vivo with oncolytic myxoma virus is efficacious against drug-resistant Vk*MYC mouse myeloma.“

The Study

“In this study, we used the Vk*MYC MM model because it faithfully recapitulates the localization of the myeloma disease within the bone marrow as well as the clinical manifestation of the disease including bone damage (paralysis), renal failure [9, 12].”

A bortezomib-resistant multiple myeloma murine cell line was examined in this study, named Vk12598. Three different strains of MYXV were tested here: vMyx-M093L-Venus, vMyx-M135KO and vMyx-hTNF. The vMyx-M093L-Venus is a wild-type MYXV that expresses Venus-tagged M093 protein as a virion component. The vMyx-M135KO virus is an unarmed and attenuated recombinant MYXV, in which the M135 gene has been deleted and the green fluorescent protein (GFP) has been inserted. The vMyx-hTNF strain is genetically modified, or “armed”, to express human tumor necrosis factor (TNF). TNF is a cytokine that induces apoptosis in various cancer cells.

First, the researchers examined the in vitro ability of these three MYXVs to bind to the Vk12598 cells in culture media. These results were then tested in vivo by first injecting the C57BL/6 mice with Vk12598 cells. Vk12598 cells were seeded for three weeks to allow the MM to progress in the mice. Then, some mice were treated with either cyclophosphamide (a common chemotherapeutic drug used to treat MM) or the compounds LCL161 and α-PD-1. Next, bone marrow cells were loaded with either vMyx-M135KO or vMyx-hTNF and transplanted into the mice.

The Results

In vitro, the researchers found that all three MYXVs did indeed bind to, infect and compromise the viability of the BOR-resistant MM cells in a relatively short period of time. In vivo, the results demonstrated that, alone, autologous bone marrow leukocytes armed ex vivo with the MYXVs (BM/MYXV) exhibited moderate therapeutic effects against the MM cells. This indicated that BM/MYXV has potential as an adjunct therapy against the MM. While little synergy was observed between Cyclophosphamide (Cy) and BM/MYXV, Cy in combination with BM/vMyx-M135KO delayed the onset of myeloma in the mice more than Cy combined with BM/vMyx-hTNF. The researchers note that these results indicate the TNF transgene may have actually interfered with efficacy.

The authors also observed a better synergistic ability between BM/vMyx-M135KO and LCL161 with α-PD-1 to control the progression of MM. This combination resulted in a significant improvement in survival rates and decreased tumor burden. When surviving mice were re-introduced to Vk12598 cells, the researchers found that they had developed acquired anti-MM immunity.

Conclusion

“Together, we show promising results in terms of therapeutic benefits of delivering oncolytic MYXV via carrier cells from autologous BM transplants, both alone or in combination with LCL161 and α-PD-1 against drug-resistant MM cells in vivo. To our knowledge, these are the first results showing therapeutic benefits of oncolytic MYXV to control and even eradicate established drug-resistant MM cells in a preclinical murine model that has previously shown excellent concordance with predicting clinical efficacy in human MM patients.”

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

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A Remote Weight Loss Strategy for Breast Cancer Survivors

March 9, 2022

Researchers Jennifer Y. Sheng and Vered Stearns discussed the results of a study that compared weight loss interventions among overweight or obese survivors of breast cancer.

Weight loss for survivors of breast cancer

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After being diagnosed with breast cancer, up to 96% of women have reported gaining weight. Medications, inactivity, food choice, and food quantity can all lead to weight gain. Studies have shown that weight gain can increase the risk of breast cancer recurrence by 40–50% and breast cancer-related mortality by 53–60%. Thus, for women with breast cancer and those who have survived breast cancer, weight management is a potentially life-saving intervention.

In an editorial paper published by Oncotarget in 2021, researchers Jennifer Y. Sheng and Vered Stearns from Johns Hopkins School of Medicine and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discussed the results of the 2020 POWER-Remote Trial—a study among breast cancer survivors on the results of a remote-based weight loss program compared with a self-directed approach. Their editorial paper is entitled, “Innovating and expanding weight loss strategies for breast cancer survivors.”

The POWER Intervention

The Practice-based Opportunities for Weight Reduction (POWER) intervention is a 12-week behavioral weight loss program designed for overweight and obese participants. The POWER program strategy focuses on physical activity and behavioral changes, nutrition education and setting individual goals. Researchers developed the POWER-remote intervention to enable participants to engage in this weight loss program remotely through weekly video conferences and phone calls. In the current editorial paper, the researchers discussed the results from a study that adapted the POWER-remote intervention for breast cancer survivors: the POWER-Remote Trial.

“The original Practice-based Opportunities for Weight Reduction (POWER) study in obese individuals with a risk for cardiovascular disease demonstrated equivalent weight loss outcomes between in-person coaching and a remote intervention [24].”

The POWER-Remote Trial

The POWER-Remote Trial was a randomized, controlled comparative effectiveness trial that evaluated the POWER-remote intervention compared to a self-directed weight loss approach among overweight or obese breast cancer survivors. Between 2013 and 2015, 87 overweight or obese women with stage 0-III breast cancer (who completed local therapy and chemotherapy) were evaluable for analysis in this study. Forty-five women were enrolled in the POWER-remote arm of the study and 42 women were enrolled in the self-directed arm.

“Our group compared the remote-based POWER intervention (telephone calls by a coach, access to online learning materials, online self-directed dietary/activity monitoring) to self-directed weight loss in overweight or obese survivors of early-stage breast cancer [25].”

Over the course of the study, the researchers found high adherence in the POWER-remote arm, with only one participant lost in follow-up. At the 12-month mark, 51% of the POWER-remote participants lost greater than or equal to 5% of their baseline body weight. Among the self-directed participants, 17% lost 5% or more of their baseline body weight. The results of this study suggest that the POWER-remote intervention is an effective weight loss strategy. It is a cost-effective, scalable and conscientious solution to assist with weight loss among many breast cancer survivors.

Conclusion

Despite the significant improvements in weight, body composition, fitness, and quality of life seen by over half of the participants in the POWER-remote arm, the researchers also pointed out a problem. The POWER-remote intervention still did not yield significant results in almost half of the other participants. Trouble sleeping was shown as a potential culprit that hindered weight loss, while many other factors inhibiting weight loss in this population are not yet fully understood.

The authors wrote that it may be necessary to further individualize or enhance the POWER intervention to achieve greater success in breast cancer survivors. They also suggested that, in some people, the POWER program may need to be augmented with pharmacological agents to aid in weight loss. In addition, the authors believe that the payer system should be reevaluated to expand coverage for obesity treatments.

“At present, I’m conducting a phase two study to determine whether an adaptor approach with pharmacotherapy can augment obesity treatment in breast cancer survivors. This study is called the A-NEW study, which stands for an Adaptive Nutrition and Exercise Weight Loss Study,” Dr. Jennifer Sheng said in a recent Behind the Study interview with Oncotarget. “We’re also looking forward to analyzing results from the COOIN study, the Cancer, Obesity, Overweight, and Insomnia study, which was led by Dr. Janelle Coughlin.”

Author Interview: Dr. Sheng discusses the research behind the editorial
Author Testimonial: Dr. Sheng describes the experience publishing with Oncotarget
Behind the Study: Transcription of Dr. Sheng’s research discussion

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

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Trending With Impact: Are NOTCH1 Variants Prognostic in Breast Cancer?

February 24, 2022

Researchers determined the prognostic ability of three NOTCH1 gene variants by incorporating them into two non-tumorigenic breast cell lines.

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The genetic changes that occur within the protein-coding gene NOTCH1 have not yet been fully studied or classified. Despite a lack in research, previous studies have suggested that NOTCH1 may be a potential target for novel cancer therapies, particularly against triple-negative breast cancer (TNBC). NOTCH1 variants in TNBC tend to cluster in the PEST region and have previously been linked to gamma secretase inhibitor (GSI) sensitivity and chemotherapy resistance.

“Furthermore, TNBC patients with increased Notch1 expression have demonstrated increased aggressive phenotypes and lower median overall survival [25].”

Since TNBC is well-known for a lack of actionable therapeutic targets, aggressive phenotypes and poor prognoses, there is an important need to develop new targeted therapies—as well as predictive markers for those therapies. Researchers from The Johns Hopkins University School of Medicine, Vanderbilt University Medical Center and The Vanderbilt-Ingram Cancer Center experimented in vitro with NOTCH1 variants and their ability to predict TNBC responsiveness to GSIs and standard of care chemotherapies. Their trending research paper was published by Oncotarget on February 16, 2022, and entitled, “NOTCH1 PEST domain variants are responsive to standard of care treatments despite distinct transformative properties in a breast cancer model.”

The Study

The researchers used three publicly available tumor-associated variant databases to identify three NOTCH1 variants that are commonly mutated in breast cancers; two variants were located in the A2441 site on NOTCH1 and the third variant was located in the PEST region of NOTCH1. To investigate the role of these NOTCH1 variants in TNBC in vitro, the team cultured two non-tumorigenic breast epithelial cell lines. Uniquely, they used an adeno-associated virus (AAV) vector to isogenically incorporate the NOTCH1 variants into the two cell lines. The researchers also developed a wildtype vector for the control arm of the study.

“In addition to the NOTCH1 variants, a targeted wildtype (TWT), which underwent the same gene targeting mechanism with a wildtype vector, was generated for both parental cell lines to act as a control.”

A standard growth factor supplemented media was used to determine if the NOTCH1 variants caused increased proliferation in the non-tumorigenic cell lines. Compared to the controls, no significant change in proliferation was observed. They also removed the epidermal growth factor (EGF) from the cells to determine if these NOTCH1 variants impart a ligand-independent proliferative advantage. In both cell lines, their results demonstrated that the A2441 variants exhibited EGF-independent growth, while the PEST NOTCH1 variant did not. Immunoblot analyses suggested that, in the absence of EGF, the A2441 NOTCH1 variants activated the MAPK pathway. These EGF-independent NOTCH1 variants (not the PEST NOTCH1 variant) conferred an invasive growth phenotype, increased migratory potential, had dysregulated 3D morphology, and significantly altered gene expression in cancer pathway genes.

Next, to measure the responsiveness and susceptibility of these variants to therapeutic agents, the cells were treated with six chemotherapeutic agents and nirogacestat—a GSI drug. Interestingly, none of the three variants demonstrated significantly different responses to the treatments when compared to one another. Furthermore, all of the variants showed sensitivity to these standard therapies used against TNBC. This suggests that these specific genetic changes within NOTCH do not have a large impact on tumor behavior and may not be useful as predictive markers for therapy response.

Conclusion

“Taken together, these data suggest that the oncogenic potential of NOTCH1 PEST domain variants depends on both variant type and amino acid location.”

Contrary to previous studies, the researchers found that the three NOTCH variants did not demonstrate significantly different responses to the GSI or the chemotherapies despite demonstrating distinct phenotypes. The lack of differential responses demonstrated by the variants in this study suggests that there is high variability among NOTCH1 variants. The prognostic potential of NOTCH1 may be dependent on the type of variant and its location, but more expansive research is necessary.

“Future studies involving meticulous characterization of an expansive panel of NOTCH1 variants in a similar model may provide mechanistic insight and predictive and/or prognostic value that is both variant type and site dependent.”

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

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Trending With Impact: New Pre-Transplant AML Treatment Combinations

February 17, 2022

Researchers aimed to improve acute myeloid leukemia (AML) patient outcomes after allo-HSCT with new pre-transplant treatment combinations.

3D Illustration of acute myeloid leukemia

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Acute myeloid leukemia (AML) is a cancer of the blood that begins in the bone marrow and progresses quickly if left untreated. AML can occur both in adults and children and is often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT is a procedure that replaces stem cells that were damaged or destroyed after radiation and/or chemotherapy treatment with stem cells from healthy donors. While allo-HSCT provides a high rate of curability in AML patients, the success of this procedure is partially dependent on the efficacy of pre-transplant treatment regimens. Researchers have identified an urgent need to determine new therapeutic approaches that provide better cytotoxicity in AML cells, without jeopardizing patient safety.

To improve AML patient outcomes after allo-HSCT, researchers fromthe University of Texas MD Anderson Cancer Center and the University of Alberta’s Cross Cancer Institute conducted a new study investigating the BCL-inhibitor ABT199/venetoclax in combination with two alkylating agents and a nucleoside analog. Their trending research paper was published by Oncotarget on February 10, 2022, and entitled, “ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells.”

“One such candidate drug is ABT199/venetoclax, a BH3-mimetic small molecule that binds to and inhibits the anti-apoptotic B-cell lymphoma 2 (BCL2) protein, preferentially causing malignant cells to undergo apoptosis [10].”

The Study

Previous studies have indicated cytotoxic properties among the alkylating agents busulfan (BU) and 4-hydroperoxycyclophosphamide (4HC), in the nucleoside analog fludarabine (Flu) and in the BCL2 inhibitor ABT199/venetoclax. The researchers in this study investigated the efficacy of ABT199/venetoclax when combined with [Bu+4HC] and [Bu+Flu] in three established AML cell lines: KBM3/Bu2506 (a Bu-resistant AML cell line established in the researchers’ laboratory), OCI-AML3 and MOLM14. They also isolated mononuclear cells taken from seven acute leukemia and myeloid dysplastic syndrome patients andexposed them to these drugs in order to assess their potential clinical implications.

“This study demonstrates a marked potentiation of the cytotoxicity of [Bu+4HC] and [Bu+Flu] when combined with the BCL2 inhibitor ABT199/venetoclax in the KBM3/Bu2506, OCI-AML3 and MOLM14 established AML cell lines.”

Study results showed that, individually, these drugs induced minimal drug-mediated apoptosis. The combination, however, of ABT199 with [Bu+4HC] or [Bu+Flu] exerted significant synergistic cytotoxicity towards AML cell lines. In the isolated mononuclear cells, a negative correlation was observed between the level of BCL2 protein and sensitivity to ABT199. The study found that the [Bu+4HC+ABT199] and [Bu+Flu+ABT199] drug combinations activated multiple biomarkers of apoptosis, increased CASPASE 3-mediated cleavage of MCL1 and MEK1/2, activated stress signaling pathways, and down-regulated pro-survival pathways.

“In summary, our results indicate strong antineoplastic activity of [Bu+4HC+ABT199] and [Bu+Flu+ABT199] towards AML cells.”

Conclusion

The combination of ABT199/venetoclax with alkylating agents and a nucleoside analog showed significant synergistic cytotoxicity towards AML cell lines in vitro. This study provides preclinical evidence for the clinical efficacy of these drug combinations and warrants further investigation in acute myeloid leukemia patients. The results of this study could lead to new, more effective treatment combinations for AML patients undergoing allo-HSCT.

“The results from this preclinical study may be used as the basis for clinical trials using [Bu+4HC+ABT199] or [Bu+Flu+ABT199] as pre-transplant conditioning therapy for high-risk AML patients undergoing allo-HSCT.”

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

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Iron Chelators in Cancer Treatment

February 10, 2022

In a review paper published in Oncotarget in 2021, researchers discuss the impact of iron chelation on cancer cell survival and the underlying mechanisms of action.

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Iron is essential for human life, however, this element can also become toxic in high doses. Contrary to iron anemia, iron overload occurs when the body accumulates more iron than it can use, and this excess iron is damaging to cells and tissues. Famous for their atypical growth patterns, cancer cells accumulate a surplus of iron to support their irregular growth and metabolism. Thus, the cancer-cell metabolism may be exploited by targeting their proclivity to require and retain iron.

“Iron chelators selectively deplete cancer cells of iron, exploiting cancer’s iron addiction – a trait displayed by a range of different cancers.”

Iron chelators are compounds that can bind to iron and facilitate iron wasting. Depriving cancer cells of iron using iron chelators has selectively cytotoxic effects in cancer cells. Some natural iron chelators include turmeric, quercetin, resveratrol, and green tea. Synthetic iron chelators include derivatives of 8-hydroxyquinoline, tachpyridine and deferoxamine. A considerable number of studies have shown that iron chelators can reverse some major catalysts and hallmarks of cancer—making iron chelators a promising treatment option for cancer patients.

Researchers Gina Abdelaal and Stephany Veuger from Northumbria University reviewed the available research literature about the impact of iron chelation on cancer cell survival and the underlying mechanisms of action. Their review paper was published by Oncotarget in 2021 and entitled, “Reversing oncogenic transformation with iron chelation.”

“This review aims to explore the underlying mechanisms of action behind iron chelator driven cytotoxicity in the context of the hallmarks of cancer established by Hanahan and Weinberg [47, 48] (see Figure 1, Supplementary Table 1). This will in turn support further research into iron chelators as a potential effective anti-cancer therapy.”

Iron Chelation Therapy

In the researchers’ review, they emphasize that iron chelation therapy has been shown to reverse multiple oncogenic hallmarks and is a promising treatment for many cancers. Studies have shown that iron chelation weakens cancer cell proliferation, induces cell cycle arrest, reactivates tumor suppressor genes, induces apoptotic signaling, inhibits stemness and Wnt/β-catenin signaling, prevents the initiation of metastasis through EMT and ROCK/MLC2 and NF-kB inhibition, and exploits and mimics genomic instability. While iron chelation has multiple targets within a cancer cell, the authors note that the NDRG1 gene has a critical role in inducing iron chelator-mediated cytotoxicity.

Figure 1: The impact of iron chelators on the hallmarks of cancer. Iron chelators have been shown to reverse many oncogenic signalling pathways associated with each hallmark of cancer with NDRG1 being a common thread. Generated through BioRender.com [47, 48].

One of the main mechanisms by which iron chelators exert their cytotoxic effects is through their ability to induce autophagy. However, this effect may both suppress and facilitate tumorigenesis. The researchers wrote that further in vivo studies must be conducted to reach a consensus about the impact of iron chelation on angiogenesis.

“In cancer cells, autophagy suppresses tumorigenesis by inhibiting cancer-cell survival and inducing cell death, but it also facilitates tumorigenesis by promoting cancer-cell proliferation and tumor growth [8,9].”

Many natural and synthetic iron chelators are currently being researched and developed. However, some early-developed iron chelators, such as deferoxamine, are effective in only some cancer patients. This is due to deferoxamine having poor lipophilicity, rapid clearance by the kidneys and poor absorption in the small intestine. Other iron chelators, such as those in the thiosemicarbazone class, are capable of inducing reactive oxygen species, causing oxidative stress. However, these chelators have only been successful in blood cancers, not in solid tumors. The researchers also spotlighted a novel iron chelator—VLX600—for its ability to target oxidative phosphorylation and initiate metabolic reprogramming.

“Cancer cells undergo a metabolic transformation known as the Warburg effect, which shifts their source of energy from oxidative phosphorylation to glycolysis. This is another trait which is exploited by iron chelators. VLX600 diminishes the ability of MCF7 and HCT116 cells to undergo oxidative phosphorylation [38].”

Conclusion

“Based on the data presented in this review iron chelators could potentially reverse many of the key hallmarks of cancer. Stripping the cells of iron impacts many cellular targets with some targets still undiscovered.”

The authors point out that the full impact of iron chelators on two remaining hallmarks of cancer, inflammation and immune evasion, have yet to be established. Additionally, the ability of iron chelators to induce both a pro-survival and tumor suppressor response in cancer cells through autophagy must be addressed. The researchers suggest that combining iron chelators with other inhibitors may be worth examination.

“We propose a combinatorial study of iron chelators with immune checkpoint inhibitors as they have shown success in clinic and could uncover more mechanisms of action.”

Click here to read the full review paper published in Oncotarget.

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What Causes Chemo Brain?

February 2, 2022

Researchers investigated potential therapeutic culprits of “chemo brain” in a trending new paper published by Oncotarget.

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A type of mental fog—known as “chemo brain”—is widely experienced by patients who have undergone cancer treatment. Cancer research institutions define chemo brain as impaired cognition, including cloudiness, memory loss and/or lack of concentration, that occurs before, during and/or after cancer treatment. This condition can negatively impact quality of life in a significant way. Chemo brain not only affects recovering individuals but also their loved ones, who often must take on additional caregiving responsibilities. Despite the name, chemotherapeutic drugs may not be the only treatments responsible for chemo brain.

A chemotherapy protective drug called amifostine is commonly used in patients and paired with chemotherapeutic agents. Amifostine functions to protect healthy cells from DNA double strand breaks (DSBs) induced by chemotherapy. Another commonly prescribed cancer treatment is called etoposide, which is a chemotherapeutic drug that also targets DSBs. Etoposide, on the other hand, functions to increase DSBs in cancer cells. Recently, researchers have suggested that DSBs could play a role in learning, memory and immediate early gene (IEG) expression. The activity of IEGs can be used to identify neural circuits involved in learning and memory processes.

“Despite their wide clinical use, there is little information about how amifostine and etoposide affect learning and memory.”

THE STUDY

Researchers from Oregon Health and Science University conducted a novel study to observe the isolated effects of these common DSB-altering agents on learning, memory and IEG expression. Systemic injections of amifostine and etoposide were examined in both male and female mice. Their research paper was published by Oncotarget in January of 2022, and entitled, “Common cancer treatments targeting DNA double strand breaks affect long-term memory and relate to immediate early gene expression in a sex-dependent manner.”

“In this study, we investigated the effects of amifostine and etoposide on hippocampus-dependent and -independent fear conditioning [23] and IEG expression in male and female C57Bl/6J mice.”

Male and female mice were systemically dosed with either saline or the one of the cancer treatments, and then trained in fear conditioning. Markers of contextual and cued memory were tested 24 hours and two weeks post-training. The study consisted of four total experiments. The first experiment examined the effects of pre-training cancer treatment injections on long-term memory. The second experiment examined the effects of post-training cancer treatment injections on long-term memory. The third experiment examined the effects of pre-training injections on cFos and Nicotinamide adenine dinucleotide phosphate (NADPH). (Increasing and inhibiting the activity of NADPH oxidase impairs learning and memory.) The fourth experiment examined the effects of pre-training cancer treatment injections on DSBs.

“Hippocampal cFos and ΔFosB are essential for contextual learning and hippocampal synaptic plasticity [12, 13].”

RESULTS

The researchers found that pre- and post-training injections of amifostine at 107 mg/kg increased long-term contextual, but not cued, freezing in male mice. Amifostine decreased hippocampal DSBs, although it did not not change cFos levels in either male or female mice. The researchers observed that post-training injections of etoposide led to long-term decreases in both contextual and cued freezing among female mice. Etoposide decreased hippocampal NADPH in females and hippocampal DSBs in both sexes. Overall, etoposide decreased hippocampal γH2Ax (a DSB repair marker), hippocampal NADPH and cortical cFos in a sex-dependent manner.

“Post-training injections of amifostine affected long-term contextual fear memory; etoposide affected contextual and cued fear memory.”

CONCLUSION

“Our results suggest that amifostine and etoposide have distinct effects on learning and memory dependent on sex and timing of administration.”

The researchers assessed the effects of these DSB-altering agents and found results suggesting that they have a direct impact on learning and memory. Their impacts varied on the basis of sex and timing of administration before or after training. The researchers suggest that future studies examine these effects on specific brain regions to clarify the underlying mechanisms driving learning and memory changes.

“Newer analogs of these drugs, such as PrC-210 [45], might reduce these side effects and improve patients’ quality of life. Future investigations are warranted to determine the role of DSBs in encoding, retrieval, and reconsolidation, and further our understanding of learning and memory processes in health and disease.”

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

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Prognostic Markers Identified in Ultra-Rare Adrenal Cancer

January 26, 2022

Researchers demonstrated the overexpression of the protein APOBEC3B in adrenocortical carcinoma. They also identified the transcription factor, known as GATA3, that directly regulates APOBEC3B.

Illustration of kidneys and adrenal glands

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Adrenocortical carcinoma (ACC) is a rare and aggressive cancer that forms in the outer layer of the adrenal gland tissue above the kidneys. According to the National Institutes of Health, the occurrence of ACC in the United States is believed to only affect one to two people per million, per year. This highly-rare disease also challenges patients and researchers due to its post-diagnosis five-year survival rate of a mere 51%.

At this time, there are no known external factors that cause this disease. Most adrenocortical tumors that have been found produce symptoms including abdominal pain and higher levels of certain hormones, inclusive of cortisol, aldosterone, testosterone, and estrogen. Any of these hormones produced in excess can have numerous troubling effects on the body and, most alarmingly, the cancer cells in the adrenal glands have the potential to travel to other organs.

Researchers—from the National Cancer Institute, Stanford University, Medical College of Wisconsin, Frederick National Laboratory for Cancer Research, and Salubris Biotherapeutics—conducted a study to learn more about ACC and the mechanisms that lead to the biological materialization of this ultra-rare disease. In 2020, their research paper was published by Oncotarget and entitled, “GATA3 and APOBEC3B are prognostic markers in adrenocortical carcinoma and APOBEC3B is directly transcriptionally regulated by GATA3.”

APOBEC3B In ACC

Previously, recent evidence confirmed the overexpression of a protein that is rightfully abbreviated as APOBEC3B (fully known as Apolipoprotein B mRNA editing enzyme catalytic subunit 3B) as a source of mutations occurring in breast, bladder, cervical, lung, head, and neck cancers. In this study the researchers used two publicly available datasets to analyze APOBEC3B gene expression in 21 normal adrenal cortices, 69 benign adrenocortical tumors and 38 ACC samples. They found that APOBEC3B is significantly overexpressed in ACC. The effects of this overexpression, in addition to a tumor mass, were consequently associated with DNA damage, reduced number of cells in S-phase arrest and increased alterations and gene mutations (particularly in the TP53 gene).

To assess the association between APOBEC3B and adrenocortical tumor growth, the team used mouse models to perform a “knockdown” or reduction, in APOBEC3B and measured the effects this had on the tumor tissue. The mice were divided into three groups of eight, and at weeks six and eight of the APOBEC3B knockdown, the researchers found significantly reduced cell proliferation and more cells in S-phase arrest.

GATA3 and APOBEC3B In ACC

The team was able to successfully knockdown APOBEC3B in mice and demonstrated that this caused a significant reduction in tumor volume. They also found in their analysis that tumors with higher expressions of APOBEC3B presented with a higher number of TP53 gene mutations. Given that the researchers were now confident that APOBEC3B is the protein that coincides with the growth of tumors in ACC, they sought to identify the mechanism responsible for regulating this protein.

After a thorough process of tests distinguishing between 90 different cancer-associated transcription factors, the team observed that the transcription factor GATA3 directly binds to the promoter region of APOBEC3B and transcriptionally regulates its gene expression in ACC.

Conclusion

In this study, the team successfully demonstrates that the protein APOBEC3B is overexpressed in ACC and causes DNA damage, alterations and mutations, and also, for the first time, that GATA3 directly regulates the expression of APOBEC3B. This confirms that the higher expression levels of both APOBEC3B and GATA3 are prognostic markers for patients with ACC.

This new information may be used in further research to develop treatments and interventions to improve the prognosis for those affected by adrenocortical carcinoma and other related disorders.

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

Go Behind the Study with co-author, Dr. Monica Varun Tyagi.

Testimonial: Dr. Tyagi describes her experience publishing with Oncotarget.

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Oncotarget’s Top 10 Most-Viewed Papers in 2021

January 21, 2022

Read the 10 most-viewed oncology-focussed papers on Oncotarget.com in 2021.

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#10: Metformin and berberine, two versatile drugs in treatment of common metabolic diseases

Authors: Haoran Wang, Chen Zhu, Ying Ying, Lingyu Luo, Deqiang Huang, and Zhijun Luo

Institutions: The First Hospital of Nanchang University, Nanchang University and Boston University School of Medicine

Quote: “Metformin has been used as a glucose lowering drug for several centuries and is now a first-line drug for type 2 diabetes mellitus (T2DM). Since the discovery that it activates AMP-activated protein kinase (AMPK) and reduces risk of cancer, metformin has drawn great attentions. Another drug, berberine, extracted from berberis vulgaris L. (root), was an ancient herbal medicine in treating diarrhea.”

#9: Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects

Author: Yuri Lazebnik

Institution: Lerna Consulting

Quote: “A distinctive feature of the SARS-CoV-2 spike protein is its ability to efficiently fuse cells, thus producing syncytia found in COVID-19 patients. This commentary proposes how this ability enables spike to cause COVID-19 complications as well as side effects of COVID-19 vaccines, and suggests how these effects can be prevented.”

#8: Physical activity and telomere length: Impact of aging and potential mechanisms of action

Authors: Nicole C. Arsenis, Tongjian You, Elisa F. Ogawa, Grant M. Tinsley, and Li Zuo

Institutions: University of Massachusetts Boston, Texas Tech University and The Ohio State University College of Medicine

Quote: “Based on the significance of telomere length in aging and the need to understand the potential association with physical activity, the purpose of this systematic review is to investigate whether physical activity and exercise influence telomere length and to discuss possible mechanisms of action.”

#7: Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer

Authors: Jayati Chakrabarti, Loryn Holokai, LiJyun Syu, Nina G. Steele, Julie Chang, Jiang Wang, Syed Ahmed, Andrzej Dlugosz, and Yana Zavros

Institutions: University of Cincinnati, University of Cincinnati College of Medicine, University of Cincinnati Cancer Institute, University of Michigan

Quote: “Tumor cells expressing programmed cell death ligand 1 (PD-L1) interact with PD-1 on CD8+ cytotoxic T lymphocytes (CTLs) to inhibit CTL effector function. In gastric cancer, the mechanism regulating PD-L1 is unclear. The Hedgehog (Hh) signaling pathway is reactivated in various cancers including gastric. Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation.”

#6: cGAS-STING pathway in oncogenesis and cancer therapeutics

Authors: Brandon Yi Da Hoong, Yunn Hwen Gan, Haiyan Liu, and Ee Sin Chen

Institutions: National University of Singapore and National University Health System (NUHS) Singapore

Quote: “The host innate immunity offers the first line of defense against infection. However, recent evidence shows that the host innate immunity is also critical in sensing the presence of cytoplasmic DNA derived from genomic instability events, such as DNA damage and defective cell cycle progression. This is achieved through the cyclic GMP-AMP synthase (cGAS)/Stimulator of interferon (IFN) genes (STING) pathway. Here we discuss recent insights into the regulation of this pathway in cancer immunosurveillance, and the downstream signaling cascades that coordinate immune cell recruitment to the tumor microenvironment to destroy transformed cells through cellular senescence or cell death programs.”

#5: Anti-aging: senolytics or gerostatics (unconventional view)

Author: Mikhail V. Blagosklonny

Institution: Roswell Park Cancer Institute

Quote: “Based on lessons of cancer therapy, here I suggest how to exploit oncogene-addiction and to combine drugs to achieve selectivity. However, even if selective senolytic combinations will be developed, there is little evidence that a few senescent cells are responsible for organismal aging. I also discuss gerostatics, such as rapamycin and other rapalogs, pan-mTOR inhibitors, dual PI3K/mTOR inhibitors, which inhibit growth- and aging-promoting pathways.”

#4: Melatonin increases overall survival of prostate cancer patients with poor prognosis after combined hormone radiation treatment

Authors: Gennady M. Zharinov, Oleg A. Bogomolov, Irina V. Chepurnaya, Natalia Yu. Neklasova, and Vladimir N. Anisimov

Institutions: N.N. Petrov National Medical Research Center of Oncology

Quote: “The antitumor and immunomodulating activities of melatonin are widely known. These activities are based upon the multifactorial mechanism of action on various links of carcinogenesis. In the present paper, the long-term results of the clinical use of melatonin in the combined treatment of patients with prostate cancer of various risk groups were evaluated.”

#3: Scent test using Caenorhabditis elegans to screen for early-stage pancreatic cancer

Authors: Ayumu Asai, Masamitsu Konno, Miyuki Ozaki, Koichi Kawamoto, Ryota Chijimatsu, Nobuaki Kondo, Takaaki Hirotsu, and Hideshi Ishii

Institutions: Osaka University and Hirotsu Bio Science Inc.

Quote: “Although early detection and diagnosis are indispensable for improving the prognosis of patients with pancreatic cancer, both have yet to be achieved. Except for pancreatic cancer, other cancers have already been screened through scent tests using animals or microorganisms, including Caenorhabditis elegans.”

#2: Inflammatory responses and inflammation-associated diseases in organs

Authors: Linlin Chen, Huidan Deng, Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Yinglun, Xun Wang, and Ling Zhao

Institution: Sichuan Agricultural University

Quote: “Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.”

#1: The goal of geroscience is life extension

Author: Mikhail V. Blagosklonny

Institution: Roswell Park Cancer Institute

Quote: “Although numerous drugs seemingly extend healthspan in mice, only a few extend lifespan in mice and only one does it consistently. Some of them, alone or in combination, can be used in humans, without further clinical trials.”

Click here to read the latest papers published by Oncotarget in Volume 13.

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Oncotarget

Can Purified Cholera Stop Obesity?

December 31, 2021

In this 2019 study, researchers investigated the effects of purified elements of cholera toxin in age-associated weight gain.

In recent years, scientists have made significant advancements to improve our understanding of the gut microbiome. This diverse environment—of somewhere around 39 trillion microorganisms living within the digestive tracts of vertebrates (including humans, and even insects)—includes bacteria, archaea, viruses, and fungi. However, a “healthy” gut microbiota remains difficult to define in humans. The contents of the gut microbiome are not only different between women and men, microbiomes differ between… everyone. Among unrelated humans, no more than 30% of the same bacterial strains are shared in the gut microbiome.

Different microbiomes can present with different biological reactions to outside factors, including infections and medications, and can even display different symptoms reacting to cancer and other diseases. Studies have repeatedly found that the gut microbiome plays important roles in human mood, sleep, metabolism, digestion, the immune and nervous systems, and in chronic inflammatory disorders, such as obesity.

“Indeed, earlier studies have shown that gut microbe-immune interactions contribute to smoldering inflammation, adiposity, and weight gain.”

The Hygiene Hypothesis

Researchers continue to find evidence to support the “hygiene hypothesis.” The hygiene hypothesis postulates that a lack of beneficial early-life microbe exposures can result in a dysregulated immune system later in life. This lack of early-life microbe exposures followed by immune imbalances may be responsible for the increase in obesity and other chronic inflammatory disorders over the past forty years.

“Systemic immune imbalances arising from the gut have been proposed as a probable cause of obesity [8].”

In 2019, researchers from Massachusetts Institute of Technology (MIT) and Aristotle University of Thessaloniki conducted a study to test using purified elements of the otherwise dangerous cholera toxin as a vaccination in mouse models. Their theory was that this safe and well-established cholera-based immune adjuvant would cause an immune system reaction that reduces the inflammation associated with age-related obesity. Their research paper was published by Oncotarget and entitled, “Consuming cholera toxin counteracts age-associated obesity.” (Go Behind the Study to learn why the researchers decided to use the cholera toxin.)

The Study

First, the researchers used both inbred and outbred mouse models to test the effects of the cholera-toxin subunit B (ctB)—a component of the Dukoral® vaccine used in humans for cholera diarrhea prevention. For each mouse model tested in the study, four different groups of eight mice each were examined: a female control group, a vaccinated female group, a male control group, and a vaccinated male group. At four weeks of age, the study mice were given three doses every-other-week of ctB at 10 micrograms. The control mice were given sham doses. The researchers found that in ctB vaccinated mice, the oral vaccination prevented age-associated weight gain compared to the control mice in both models.

Next, the researchers used an obese mouse model to test the effects of ctB dosing in early-life and to test the effects of transfering their gut flora into another mouse. The researchers found that the obese-mouse microbiome was sufficient to trigger obesity and inflammation in other mice when compared to sham-dosed control mice. In the obese mouse model, ctB dosing in early life also inhibited age-associated weight gain. This probiotic inhibited weight gain in mice dosed in early-life, and also in mice dosed in adulthood.

“Although we discovered dramatic benefit after early-life exposures to ctB, mice were also significantly slimmer when dosed with ctB for the first time during adulthood at 12-wks-of-age or 24-wks-of-age.”

Conclusion

The researchers found that purified elements of the cholera toxin stabilized immunity, through the gut microbiome, and inhibited age-associated obesity in multiple mouse models. Further studies are necessary to determine the degree to which an early-life microbe exposure such as this impacts immunity versus first-time adulthood exposures. Humans have been taking pre- and probiotics for quite some time without a strong grasp of exactly how these microbe infusions work. This research contributed to a better understanding of how humans can modulate our own gut microbiome to improve many aspects of our health and well-being.

“This type of microbe-immune re-programming may ultimately target other diseases linked with obesity and inflammation such as diabetes [19], multiple sclerosis [64], and cancer [25].”

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

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Oncotarget

Could Metformin and Rapamycin Replace Maintenance Chemotherapy?

December 16, 2021

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

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

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

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

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

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

The Study

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

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

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

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

Results and Conclusion

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

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

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

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

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