Tagged: Trending With Impact

Oncotarget

Novel Therapeutic Strategies Against Endometrial Cancer

April 6, 2022

In a new study, researchers investigated the role of the (pro)renin receptor in endometrial cancer cell growth.

In a new study, researchers investigated the role of the (pro)renin receptor in endometrial cancer cell growth.
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In the United States and worldwide, the incidence and mortality rates of endometrial cancer among women have been increasing in recent years. While endometrial cancer is highly treatable, the primary treatment is a surgical hysterectomy. Hysterectomies can have serious side effects and painful personal consequences.

The rise of this gynecological cancer has driven researchers to investigate viable targets and biomarkers for use in endometrial cancer diagnosis, prognosis prediction and alternative therapeutic strategies. In a new study, researchers—from the University of Newcastle, University of Technology Sydney, Monash University, and the University of Melbourne—investigated the (pro)renin receptor ((P)RR) and its role and interactions in the biology of endometrial cancer. Their trending research paper, published in Oncotarget on April 1, 2022, was entitled, “Role of the prorenin receptor in endometrial cancer cell growth.”

The Study

The ATPase H(+)-transporting lysosomal accessory protein 2 (ATP6AP2) gene encodes the (P)RR, and the terms can be used interchangeably. The (P)RR is a membrane protein that plays a key role in activating the renin-angiotensin system (RAS). It is widely expressed in various tissues and organs, such as the kidney, heart, lung, and endometrium. In endometrial cancer, the (P)RR has been shown to be overexpressed in cancerous tissue compared to normal endometrium tissue. Expression levels of this receptor are associated with endometrial cancer progression and poor prognosis. However, the precise role of the (P)RR in endometrial cancer has remained largely unknown.

In this in vitro analysis, the researchers first conducted a proteomic screening of the ATP6AP2 protein and mRNA expression in three endometrial cancer cell lines: Ishikawa, AN3CA and HEC-1-A. To silence (P)RR expression in each of the three cell lines, the team employed an siRNA-mediated knockdown of ATP6AP2. Next, they used an xCELLigence RTCA DP instrument that measures cell invasion and migration to evaluate the impact of (P)RR knockdown on cellular proliferation. They then used a resazurin assay to examine the effects of (P)RR knockdown on cancer cell viability.

A proteomic screening was also carried out to explore potential pathways (P)RR is involved in in the physiology of endometrial cancer. In addition, the enzyme-linked immunosorbent assay (ELISA) was used to measure circulating soluble prorenin receptor (s(P)RR) levels in the endometrial cancer cell lines (before and after the knockdown of (P)RR expression) and in plasma and uterine fluid samples donated by endometrial cancer patients.

The Results

This study was the first to report the mRNA and protein expression of (P)RR in three endometrial epithelial cancer cell lines. The results showed that the (P)RR was critical for endometrial cancer cell growth—contributing both to its cell viability and proliferative capacity. However, the data confirmed their previous observations that (P)RR mRNA and protein levels do not correlate with tumor grade in primary endometrial tumor samples. The researchers stated that the (P)RR’s contribution to endometrial cancer progression is likely mediated through proteins reduced after (P)RR expression knockdown, such as MGA, SLC4A7, SLC7A11, or DHRS2.

“Notably, (P)RR mRNA and protein levels were independent of tumour grade, with the highest expression detected in Ishikawa cells (grade 1), followed by AN3CA cells (grade 3) and finally HEC-1-A cells (grade 2).

They also observed that s(P)RR levels in their plasma samples were significantly higher in patients with endometrial cancer than in age-matched controls. Intriguingly, as cancer grade increased, so did s(P)RR levels. This indicated that s(P)RR may be a viable predictive or diagnostic marker for patients with endometrial cancer.

“Our data confirms that the (P)RR is important for endometrial cancer development, contributing to both its viability and proliferative capacity. Moreover, our quantitative proteomics approach uncovered several putative protein interactions and pathways that rely on (P)RR for disease progression and may represent novel therapeutic targets in the treatment of endometrial cancer. Finally, we contend that circulating s(P)RR levels may have substantial potential as a novel biomarker for cancer diagnosis and prognosis.”

Conclusion

This study sheds new light on the role of the (P)RR in endometrial cancer. The researchers suggest that future studies should aim to vet their findings in endometrial cancer patients.

“Collectively, our data indicate that targeting the (P)RR by an siRNA approach (such as in this study) or with an alternative anti-(P)RR monoclonal antibody approach currently being explored by Wang et al. [29] may be a viable therapeutic strategy against endometrial cancer.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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Oncotarget

Trending With Impact: Interrelated Oncogenic Pathways in Osteosarcoma

March 24, 2022

Researchers evaluated the roles and relationship between two cancer-related signaling pathways in osteosarcoma.

A child x-ray elbow ​Lateral, AP view of the forearm caused by bone cancer(osteosarcoma) of the ulna.
A child x-ray elbow ​Lateral, AP view of the forearm caused by bone cancer(osteosarcoma) of the ulna.

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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Osteosarcoma (OS) is a fairly uncommon type of bone cancer that primarily develops in the long bones found in the arms and legs. While most osteosarcomas occur in patients between the ages of 10 and 30 years old, half of all osteosarcomas develop in children. Osteosarcoma is a genetically diverse cancer that lacks a consistent targetable mutation—saddling patients and researchers with major challenges when it comes to treatment options.

“Despite their high mutation burden, OS has proven surprisingly recalcitrant to the numerous immunotherapies that have revolutionized the treatment of other mutation-high cancers.”

The lack of consistent therapeutic targets in osteosarcoma has driven researchers to investigate the role of oncogenic signaling pathways in this disease. In a trending research paper published in Oncotarget on March 9, 2022, researchers from The University of Texas’ MD Anderson Cancer Center and Rice University evaluated osteosarcoma and two cancer-related signaling pathways: IGF-1/mTOR and YAP/TAZ (the Hippo Pathway). Their paper was entitled, “Correlation of nuclear pIGF-1R/IGF-1R and YAP/TAZ in a tissue microarray with outcomes in osteosarcoma patients.”

The Study

Oncogenic signaling pathways are often deregulated in cancer, which means that these pathways can potentially be targeted and exploited for therapeutic purposes. The insulin/insulin-like growth factor (IGF) signaling pathway to mTOR (IGF-I/mTOR) is a well-known oncogenic pathway that is often deregulated in solid tumors. The YAP/TAZ (Hippo pathway) plays an important role in organ size control and tissue regeneration.

In this study, the researchers retrospectively evaluated the correlation between nuclear pIGF-IR/IGF-IR, YAP/TAZ expression and outcomes in patients with osteosarcoma. Effectors and pathways were investigated among 37 post-treatment human osteosarcoma tumor specimens. The specimens were analyzed using tissue microarray (TMA), confocal imaging, quantitative image analysis, nuclear staining, the Cox proportional hazards model, and Kaplan–Meier analysis. Researchers who evaluated images of de-identified patient samples were blind to patient demographics and outcomes until after analysis was complete.

The Results

Their results demonstrated that nuclear IGF-1R and YAP/TAZ are interrelated in human osteosarcoma. Their findings also showed that high nuclear-phosphorylated IGF-1R and low YAP nuclear-to-cytoplasmic (N:C) ratio are potentially negative prognostic indicators of overall survival in osteosarcoma patients.

“While sole targeting of the IGF/PI3K/mTOR cascade has had limited success in early phase osteosarcoma trials, our study suggests that nuclear pIGF-1R might serve as a prognostic biomarker to identify osteosarcoma patients that have an especially poor prognosis.”

Findings from this study may have revealed a clinically important relationship between these pathways in osteosarcoma. Osteosarcoma is currently treated with a combination of surgery, chemotherapy and radiation therapy. However, this study suggests that therapies targeting the IGF-I/mTOR and/or YAP/TAZ pathways may improve the diagnosis and treatment of patients with osteosarcoma.

Conclusion

The researchers were forthcoming about limitations in their study. They recognized that the sample size was relatively small and the study design only involved post-treatment specimens and retrospective analysis. However, the authors note that the likely crosstalk observed between the YAP/TAZ and IGF/PI3K/mTOR pathways is an important finding. They hypothesize that a dual-targeted pathway approach may have synergistic antineoplastic activity.

“Given the rarity of osteosarcoma, clinical validation of our results will almost certainly require the active participation of national and international high-volume cancer centers.”

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

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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

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Oncotarget

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

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Oncotarget

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.

Breast cancer illustration
Breast cancer illustration

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

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Oncotarget

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

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

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Oncotarget

What Causes Chemo Brain?

February 2, 2022

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

What Causes Chemo Brain?

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

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Oncotarget

Gene Mutations and Neoantigens in Head and Neck Tumors

January 13, 2022

The aim of this exploratory study was to characterize the genomic and neoantigen changes in 23 paired primary and recurrent head and neck cell squamous-cell carcinomas.

X-Ray film of neck - front and side
True colour X-Ray film of neck – front and side
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Head and neck cancer is a group of various tumors located in the oral cavity, oropharynx, larynx, and hypopharynx. Head and neck cell squamous-cell carcinomas (HNSCC) often result from tobacco use or human papillomavirus (HPV+) infection. In locally advanced HNSCC, the current therapies used are combined surgery, radiotherapy and chemotherapy. Despite the use of traditional treatments, up to 50% of patients relapse due to the increase in mutational burden as HNSCC advances. Few studies have investigated the therapeutic potential of neoantigens in HNSCC tumors.

“Prior work has characterized changes in the mutation burden between primary and recurrent tumors; however, little work has characterized the changes in neoantigen evolution.”

Neoantigens are new proteins/antigens that form on cancer cells after mutations occur in the tumor DNA. Certain neoantigens can promote anti-tumor immune responses and are potentially capable of controlling tumor progression. In an effort to characterize genomic and neoantigen changes in patients with HNSCC, researchers—from Washington University in St. Louis, Columbia University, St. Louis Children’s Hospital, and Siteman Cancer Center—investigated 23 paired primary and recurrent HNSCC tumors. Their paper, entitled, “Genomic and neoantigen evolution from primary tumor to first metastases in head and neck squamous cell carcinoma,” was chosen as the cover paper for Oncotarget’s Volume 12, Issue #6.

Patients and Samples

The researchers identified 23 biopsies from patients originally diagnosed with locally advanced HNSCC. Of the 23 patients in this study, 17 were male and 14 were tobacco smokers. The distribution of primary tumor location was nine in the oral cavity, seven in the oropharynx, six in the larynx, and one in the hypopharynx. The researchers note that all seven oropharyngeal primary tumor patients were HPV+. Each of the 23 patients received some combination of traditional treatment. Of these 23 patients, DNA and total RNA were independently extracted—totaling 69 samples. Twenty-three samples were from germlines, 23 were from primary tumors and 23 were from recurrent/metastatic tumors.

“To understand the recurrent mutation effect between primary and recurrent/metastatic tumors, we extract recurrently mutated genes (>1 sample mutated gene) from primary and recurrent/metastatic samples, separately.”

Recurrently Mutated Genes

The 23 germline blood samples were used in whole-exome sequencing (WES) data. The researchers also generated WES data using 46 paired primary and recurrent/metastatic samples from paraffin blocks and performed RNA sequencing successfully for 31 samples. After conducting RNA sequencing, they used Kallisto to predict gene expression in 16 primary tumors and 15 recurrent/metastatic tumors. A general trend showed that more mutations were within recurrent/metastatic tumors than in primary tumors. They performed KEGG pathways analysis to determine whether mutations occurred in pathways related to metastasis.

“Notably, ECM-receptor interaction pathway was extremely significant in recurrent/metastatic samples meaning that genes related to this pathway are more highly mutated than other pathway mutations in recurrent/metastatic samples.”

The TP53 gene was found to be the highest mutated driver gene in both sample groups, and the researchers identified BRCA1 and NOTCH1 as highly mutated driver genes in primary tumor samples. In recurrent/metastatic tumors, PIK3CA, ARID1A, RASA1, TSC2, and ERBB4 were mutated at higher rates than in primary tumor samples.

Infiltration of Immune Cells

To determine the infiltration of immune cells in primary tumors versus recurrent/metastatic tumors, the team performed immunohistochemistry. No significant differences in CD3+ cells, activated T cells, cytotoxic T cells, or  CD3+ FOXP3+ cells were found. A significant increase of PD-L1 (an immune checkpoint protein) was found in recurrent/metastatic tumors. Upon further examination of immune checkpoint molecules, the researchers found a decrease in the expression of PDCD1 and CTLA4, with PDCD1 significantly decreased.

“We next sought to determine if genes containing neoantigens were shared between patients. Most neoantigens were unique to an individual tumor.”

Neoantigen Trends

In order to predict neoantigens among 46 tumor samples, this team utilized OptiType and MuPeXI to define the candidate neoantigens. Most patients had unique neoantigens based on the individual tumor type, however, the researchers’ analysis identified multiple patients with neoantigens in shared genes. They found neoantigens in six genes shared between four or five patients. (Three genes were among primary tumors: RYR3, DNAH7 and TTN; and three genes were among recurrent tumors: TNN, PIK3CA and USH2A.) They found that, compared to patients without them, patients who shared neoantigens in these genes tended to have increased neoantigens, CD3+ CD8+ T cell infiltration and duration of survival with HNSCC.

“These patients have increased total neoantigens, and a trend toward increased duration of survival with disease, infiltration of CD8 cells, and CTL activity. This suggests HNSCC neoantigens can stimulate an anti-tumor immune response.”

Conclusion

In conclusion, six genes with predicted neoantigens were found in four or more HNSCC patients. The researchers explained that while there is considerably more work needed in order to expand on their results from this small sample, the observation of neoantigens in these shared genes is significant.

“This raises the possibility that the presentation of certain neoantigens are important for control of tumor growth. This small exploratory study will provide the justification for a larger study of neoantigens in HNSCC.”

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

Behind the Study: Drs. Brian Van Tine and Charles Schutt discuss this research.

ONCOTARGET VIDEOS: YouTube | LabTube | Oncotarget.com

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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.

3D illustration of the gut microbiome
3D illustration of the gut microbiome

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.

ONCOTARGET VIDEOS: YouTube | LabTube | Oncotarget.com

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

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Scientific Integrity
Oncotarget

Trending With Impact: Unconventional Method Effectively Targets NSCLC

October 4, 2021

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

New ideas

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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Listen to an audio version of this article

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

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

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

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

THE STUDY

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

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

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

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

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

CONCLUSION

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

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

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

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

Read the press release here

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

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

Oncotarget

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

August 26, 2021

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

3D illustration of lung cancer

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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Listen to an audio version of this article

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

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

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

The Study

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

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

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

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

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

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

Conclusion

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

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

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

YOU MAY ALSO LIKE: More Oncotarget Videos on LabTube

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

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