Tag Archives: #colorectalcancer

Oncotarget: RAS Reversion in Colorectal Cancer Patients Treated With Bevacizumab (Medicine)

Oncotarget published “Occurence of RAS reversion in metastatic colorectal cancer patients treated with bevacizumab” which reported that a disappearance of RAS mutations in the plasma of about 50% of mCRCs treated with bevacizumab-based chemotherapy has been reported.

Using next-generation sequencing and real-time PCR approaches, these authors characterized the primary tumor and paired liver metastases in 28 RAS mutant mCRCs.

RAS mutant alleles are at the same percentage in PT and liver metastases in the control group, while a significant reduction of the level of RAS mutations was detected in 57.1% of cases in group 1 and in 8.3% of cases in group 2. Differences among groups are statistically significant.

Most mCRC patients treated with bevacizumab-containing regimens experience a strong reduction of RAS mutant cells, suggesting bevacizumab as particularly active against RAS mutant cells.

This Oncotarget finding might have potential therapeutic implications, as anti-EGFR could be reconsidered in primarily RAS mutant patients reverted to a wild-type status after bevacizumab exposure.

This Oncotarget finding might have potential therapeutic implications, as anti-EGFR could be reconsidered in primarily RAS mutant patients reverted to a wild-type status after bevacizumab exposure.

Dr. Samantha Epistolio from The EOC said, “The overall survival (OS) for patients with metastatic colorectal cancer (mCRC) has markedly improved within the last 2 decades, reaching approximately 30 months.

Thus, it is crucial to perform an extended RAS and BRAF mutation analysis before considering EGFR inhibitors in mCRC patients.

In first-line, data support the use of anti-EGFR MoAbs in patients with left-sided, RAS and BRAF wild-type tumors, whilst bevacizumab is preferred in combination with chemo-doublets or -triplet in RAS/BRAF mutated tumors or RAS/BRAF wild-type right-sided primaries.

More recently, two intriguing studies showed that cetuximab sensitivity might be restored either in RAS/BRAF wild-type mCRC patients who acquired resistance to cetuximab-based therapy in first-line therapy or in those with primarily RAS mutated tumors treated with bevacizumab-containing regimens in second-line.

These studies may lead to the hypothesis that anti-angiogenic agents through action on RAS mutated cells could revert tumors from RAS mutant to RAS wild-type status, which theoretically could lead to the possibility to treat these patients with anti-EGFR MoAbs, otherwise precluded.

To substantiate these findings at tissue level, here they analyzed molecular changes in RAS mutated mCRC patients treated with chemotherapy alone or in combination with bevacizumab, by examining tumor tissue samples before and after the systemic therapy using two independent methodologies, next-generation sequencing and real-time PCR.

The Epistolio Research Team concluded in their Oncotarget Research Output, “this retrospective observational study, strongly suggests the existence of a link between bevacizumab exposure and RAS status changes in mCRC patients. In addition to other reports using liquid biopsies, our findings on tissue samples corroborate the hypothesis that bevacizumab could revert RAS mutant mCRC to a wild-type pattern, conceptually opening to the possibility to treat with anti-EGFR MoAbs mCRC patients otherwise excluded based on initial RAS mutated status.

DOI – https://doi.org/10.18632/oncotarget.27965

Full text – https://www.oncotarget.com/article/27965/text/

Featured image: Real-time PCR (SensiScreen™) amplification curves of patient 8 (group 2). X-axis reports real-time PCR cycles and Y-axis reports relative fluorescence unit (RFU). In red is represented the amplification of the reference gene and in blue the amplification of the specific mutation (G13D). (A) Curves obtained from amplification of DNA extracted from sample 8PT; (B) Curves obtained from amplification of DNA extracted from sample 8LM1. Abbreviations: 8LM1, liver metastasis sample (patient 8); 8PT, primary tumor sample (patient 8); RFU, relative fluorescence unit © Epistolio et al.


Reference: Epistolio S., Cefalì M., Spina P., Molinari F., Movilia A., Cergnul M., Mazzucchelli L., Dosso S. De, Frattini M., Saletti P. Occurence of RAS reversion in metastatic colorectal cancer patients treated with bevacizumab. Oncotarget. 2021; 12: 1046-1056. Retrieved from https://www.oncotarget.com/article/27965/text/


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Hijacked Immune Activator Promotes Growth & Spread Of Colorectal Cancer (Biology)

Through a complex, self-reinforcing feedback mechanism, colorectal cancer cells make room for their own expansion by driving surrounding healthy intestinal cells to death – while simultaneously fueling their own growth. This feedback loop is driven by an activator of the innate immune system. Researchers from the German Cancer Research Center (DKFZ) and the University of Heidelberg discovered this mechanism in the intestinal tissue of fruit flies.

Maintaining the well-functioning state of an organ or tissue requires a balance of cell growth and differentiation on the one hand, and the elimination of defective cells on the other. The intestinal epithelium is a well-studied example of this balance, termed “tissue homeostasis”: Stem cells in the intestinal crypts constantly produce progenitor cells that further differentiate to replace the rapidly deteriorating mature cells of the intestinal mucosa.

Growth requires a constant dynamic reorganization of tissue architecture: Defective cells must be displaced from the tissue, also by mechanical forces. Tumor cells disrupt this finely balanced structure: They aggressively make room for their own expansion. Until now, it was not understood how exactly they do this.

Jun Zhou, Erica Valentini and Michael Boutros from the German Cancer Research Center and the University of Heidelberg have now investigated these processes in the intestinal epithelium of the fruit fly, which has a similar structure to the intestine of mammals. By blocking the important BMP signaling pathway, the researchers triggered numerous tumors in the fly intestine. Using this model, they uncovered how cancer cells accelerate their own growth through a sophisticated, self-reinforcing feedback effect.

First, tumor cells tear apart the tissue structure by acting on cell adhesion. The resulting altered mechanical adhesion of the intestinal cells activates a stress-sensitive signaling pathway in neighboring intestinal cells, which in turn causes the activation og genes that promote programmed cell death (apoptosis): The team was able to detect large amounts of proteins that initiate aopotosis in the intestinal cells surrounding individual tumor cells.

Presumably due to cytokines released by dying intestinal cells, the growth-promoting JAK/Stat signaling pathway is activated in tumor cells, leading to further tumor spread.

The team also found that the immune activator PGRP-LA is required for this process. When PGRP-LA is turned off, fewer colon cells die through apoptosis and tumor growth also slows down. “The colon cancer cells apparently hijack a signaling molecule of the innate immune system and misuse it for their own purposes. In this way, they kill two birds with one stone: they make room for their expansion by eliminating intestinal cells in their environment – and additionally fuel their own growth,” explains study leader Michael Boutros. Future studies will determine whether the same mechanisms also play a role in the spread of human intestinal tumors.

Featured image: Graphical abstract by Jun Zhou et al.


Reference: Jun Zhou, Erica Valentini und Michael Boutros: Microenvironmental innate immune signalling and cell mechanical responses promote tumor growth. Developmental Cell 2021, DOI: 10.1016/jdevcell.2021.06.007


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Intestinal Polyps in Close Relatives Can Increase Risk of Colorectal Cancer (Medicine)

Cancer of the colon and rectum is one of the deadliest forms of cancer, and has in recent years affected growing numbers of young people. In the largest registry study to date, researchers at Karolinska Institutet and Harvard University in the USA demonstrate a possible connection between colorectal polyps in close relatives and the risk of developing colorectal cancer. The study, which is published in The British Medical Journal, is of potential consequence for screening procedures.

Colorectal cancer is the second deadliest form of cancer in the world, according to the World Health Organisation (WHO). While lifestyle factors, such as overweight and sedentariness, increase the disease risk, there is also a known hereditary factor.

Most people diagnosed with the disease are over 65, but in a growing number of countries the proportion of young people affected is increasing.

Local colorectal cancer can be treated with a good prognosis; prospects are much worse, however, for patients with metastases. In Sweden, people over 65 are offered colonoscopy screening, but more knowledge is needed about which individuals should be offered this prophylactic examination. 

Patient data from ESPRESSO

The disease is preceded by polyps in the mucosa of the colon. Researchers at Karolinska Institutet and Harvard University have now conducted the largest registry study to date on the relationship between colorectal cancer, and having a first-degree relative (i.e. parents and siblings) with a  colorectal polyp. 

The study included 68,060 patients with colorectal cancer and 333,753 healthy controls matched for parameters such as age and sex. Data on colorectal cancer and polyps were sourced from the ESPRESSO (Epidemiology Strengthened by Histopathology Reports in Sweden) cohort.

All other patient data were drawn from Swedish healthcare registries. The researchers also took the hereditariness of colorectal cancer into account. They found that approximately 8.4 per cent of the participants with colorectal cancer had a sibling or parent with colorectal polyps, as opposed to 5.7 per cent of the control group.

Several hereditary risk relationships

The results show that heredity for colorectal polyps had a 40 per cent increased risk of colorectal cancer. The researchers found what appear to be several hereditary risk relationships.

Mingyang Song. Photo: Harvard University.

“The risk was double in people with at least two first-degree relatives with polyps or a first-degree relative who had a colorectal polyp diagnosed before the age of 60.” says the study’s first author Mingyang Song, researcher at Harvard University.

A weakness of the study is the lack of information on other risk factors of colorectal cancer, such as lifestyle factors as well as the size and spread of the polyps. More research is now needed to corroborate the results.

Jonas F. Ludvigsson. Photo: Ulf Sirborn

“If additional studies reveal a link between a family history of polyps and the risk of colorectal cancer, it is something to take into account in the screening recommendations, especially for younger adults,” says Jonas F. Ludvigsson, paediatrician at Örebro University Hospital and professor at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. “I really hope that this study can help doctors in Sweden and elsewhere identify patients at a higher risk of colorectal cancer.”

The study was financed by the National Institutes of Health and the American Cancer Society. Jonas F. Ludvigsson heads an unrelated study commissioned by the Swedish IBD Quality Registry (SWIBREG) financed by Janssen. There are no other reported conflicts of interest.

Featured image: Illustration of intestinal polyps that can cause colorectal cancer. Illustration: Getty Images.


Publication

“Risk of colorectal cancer in first degree relatives of patients with colorectal polyps: nationwide case-control study in Sweden”. Mingyang Song, Louise Emilsson, Bjorn Roelstraete, Jonas F. Ludvigsson, British Medical Journal, May 4 2021, doi: 10.1136/bmj.n877.


Provided by Karolinska Institute

Average-risk Individuals May Prefer Stool-based Tests Over Colonoscopy for Colorectal Cancer Screening (Medicine)

When given a choice, most individuals with an average risk of colorectal cancer said they would prefer a stool-based screening test for colorectal cancer over colonoscopy, the method most often recommended by health care providers, according to results published in Cancer Prevention Research, a journal of the American Association for Cancer Research.

Although colorectal cancer is the second most frequent cause of cancer-related death in the United States, about one-third of eligible American adults have never completed a colorectal cancer screening test, explained lead author Xuan Zhu, PhD, senior health services analyst at the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Zhu added that colorectal cancer screening is particularly underutilized by individuals experiencing socioeconomic disadvantages, racial and ethnic minorities, and certain age groups.

The U.S. Preventive Services Task Force (USPSTF) recommends several colorectal cancer screening methods for adults ages 50 to 75 with an average risk for this disease, and the USPSTF draft guideline update released in October 2020 recommends lowering the age of screening initiation to 45. The three most common tests are an annual fecal immunochemical test or fecal occult blood test (FIT/FOBT) that detects blood in the stool; the multitarget stool DNA (mt-sDNA) test (Cologuard), completed every three years, which detects altered DNA from cancer cells, precancerous polyps, or blood in the stool; and a colonoscopy every 10 years, which involves a gastroenterologist examining the colon with a camera and removing any precancerous polyps while a patient is under sedation.

“Previous research has shown that fewer patients complete colorectal cancer screening when only colonoscopy is recommended compared to when stool-based options are also recommended,” said Zhu.

In this study, Zhu and colleagues evaluated patient preferences for colorectal cancer screening through a survey conducted in collaboration with the National Opinion Research Center at the University of Chicago. The survey included short descriptions of FIT/FOBT, mt-sDNA, and colonoscopy, and asked a nationally representative sample of adults ages 40 to 75 to choose between two options presented at a time. A total of 1,595 respondents completed the survey. The researchers focused their analysis on a subgroup of 1,062 respondents aged 45 to 75 with an average risk of colorectal cancer.

When presented with a choice, 66 percent of respondents said they preferred mt-sDNA over colonoscopy, and 61 percent said they preferred FIT/FOBT over colonoscopy. When asked to choose between the two stool-based options, 67 percent indicated a preference for mt-sDNA over FIT/FOBT.

The investigators also examined differences in patient preferences across sociodemographic characteristics, access to health care, awareness of colorectal cancer screening, and prior experience completing a test. While mt-sDNA was preferred over colonoscopy for all age groups examined, a larger proportion of older adults (ages 65 to 75 years) said they preferred colonoscopy compared to those in younger age groups (ages 45 to 54 years).

Similarly, the preference for mt-sDNA over colonoscopy was higher among non-Hispanic white individuals compared with non-Hispanic Black and Hispanic individuals. Half of Hispanic and non-Hispanic Black respondents preferred stool-based tests over colonoscopy, with a preference for mt-sDNA over FIT/FOBT. Zhu said the observed differences among age and racial/ethnic groups might have reflected variations in preferences or disparities in access to information about newer testing methods.

Respondents without insurance were 2.5 times more likely to prefer less expensive stool-based tests over colonoscopy. The overall awareness of stool-based tests was about 60 percent, compared to 90 percent for colonoscopy, indicating that there is an opportunity to improve patient education about stool-based options, Zhu noted. Study participants who were aware of stool-based tests were two times more likely to prefer mt-sDNA over FIT/FOBT, and those who had previously had a stool-based test were 2.8 times more likely to choose FIT/FOBT over colonoscopy. By contrast, those who had previously had a colonoscopy were less than half as likely to prefer a stool-based test over colonoscopy and those who had a provider recommend colonoscopy in the past 12 months were 40 percent less likely to prefer mt-sDNA over colonoscopy.

“The best colorectal cancer screening test is the one that patients are most likely to complete,” Zhu said.

The findings highlight the importance of patient education about available screening options and taking patients’ needs, preferences, and values into account in shared decision-making discussions to increase colorectal cancer screening rates, Zhu added. “Providing patients with as-needed navigation support, from initiation of screening to completion of a colonoscopy after stool-based tests show abnormal results may increase screening completion and adherence.”

Limitations of this study include the observational design, meaning that causal relationships cannot be inferred, the reliance on self-reported data rather than objective measures, and limiting the scope of the study to the three colorectal cancer screening tests most commonly recommended by health care providers.

The study was supported by funding provided by Exact Sciences Corporation and the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery. Zhu declares no conflicts of interest.


Reference: Xuan Zhu, Philip D. Parks, Emily Weiser, Kristin Fischer, Joan M. Griffin, Paul J. Limburg and Lila J. Finney Rutten, “National Survey of Patient Factors Associated with Colorectal Cancer Screening Preferences”, Cancer Prevention Research, 2021. DOI: 10.1158/1940-6207.CAPR-20-0524


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Pembrolizumab Slows MSI-H-dMMR Metastatic CRC (Medicine)

For the first-line treatment of microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) metastatic colorectal cancer, pembrolizumab is superior to chemotherapy for prolonging progression-free survival, according to a study published in the Dec. 3 issue of the New England Journal of Medicine.

Pembrolizumab ©Wikipedia

Thierry André, M.D., from Sorbonne Université and Hôpital Saint Antoine in Paris, and colleagues conducted a phase 3, open-label trial involving 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment. Participants were randomly assigned in a 1:1 ratio to receive either pembrolizumab (200 mg every three weeks) or chemotherapy every two weeks.

After a median follow-up of 32.4 months, at the second interim analysis, the researchers found that pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 versus 8.2 months; hazard ratio, 0.60). After 24 months of follow-up, the estimated restricted mean survival was 13.7 months compared with 10.8 months. Overall, 56 and 69 patients in the pembrolizumab and chemotherapy groups, respectively, had died as of the data cutoff date; data on overall survival were still evolving. An overall response was seen in 43.8 and 33.1 percent of patients in the pembrolizumab and chemotherapy groups, respectively. Among those with an overall response, 83 and 35 percent of those in the pembrolizumab and chemotherapy groups, respectively, had ongoing responses at 24 months.

“These data represent another step forward for biomarker-driven studies targeting MSI-H-dMMR colorectal cancers,” the authors write. “Pembrolizumab should be considered an option for initial therapy for patients with MSI-H-dMMR metastatic colorectal cancer.”

Several authors disclosed financial ties to pharmaceutical companies, including Merck, which manufactures pembrolizumab and partially funded the study.

References: Thierry André, Kai-Keen Shiu, Tae Won Kim, Benny Vittrup Jensen, Lars Henrik Jensen, Cornelis Punt, Denis Smith, Rocio Garcia-Carbonero, Manuel Benavides, Peter Gibbs, Christelle de la Fouchardiere, Fernando Rivera, Elena Elez, Johanna Bendell, Dung T. Le, Takayuki Yoshino, Eric Van Cutsem, Ping Yang, Mohammed Z.H. Farooqui, Patricia Marinello, and Luis A. Diaz, “Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer”, The New England Journal of Medicine, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2017699

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Research Reveals Why Some Tumors Have Different Makeup of Cells (Medicine)

Molecular changes in cells called fibroblasts, which help provide support for tissues throughout the body, may explain why one type of colon cancer doesn’t respond to therapy, according to a team of researchers from Weill Cornell Medicine. Targeting these cells may be a way to make treatment more effective.

Image of a colon tumor in mice. Cancer-associated fibroblasts (red) help the tumor grow more aggressively and help block the immune system response against it. ©Weill Cornell Medicine

In a study published Nov. 17 in DevelopmentalCell the investigators examined cells called fibroblasts in CMS4, the most aggressive and difficult-to-treat form of colorectal cancer, to determine how these cancer-associated cells acquire traits that allow them to support malignancy in neighboring cells. CMS4 affects about a third of all colorectal cancer patients.    

“There are two important components to this study,” said co-senior author Dr. Jorge Moscat-Guillen, Homer T. Hirst III Professor of Oncology in Pathology and Vice-Chair for Experimental Pathology. “First, we have shown in a mechanistic way how these cancer-associated fibroblasts acquire the characteristics that they have. Second, we confirmed that what we discovered in our lab models also applies to patients, which begins to suggest how these findings could be useful in the clinic.”

Tumors are made up not only of cancer cells, but many other kinds of cells as well. These other cell types can influence how a tumor behaves and can have a profound effect on whether it responds to therapy, including treatment with immunotherapy.

Fibroblasts are present throughout the body. In the colon, they are part of the contractile system that is key to digestion. Researchers have known that the presence of fibroblasts inside a tumor can impact its behavior, especially influencing whether tumors respond to immune checkpoint blockade drugs. These are drugs that take the brakes off the immune system and allow it to attack cancer. “Until now, a pending question in the field has been what causes these tumors full of fibroblasts to develop,” said co-senior author Dr. Maria Diaz-Meco, a professor in the Department of Pathology and Laboratory Medicine.

Graphical abstract by Hiroaki et al.

Previous research from Dr. Moscat and Dr. Diaz-Meco reported the creation of a mouse model that mimics CMS4 colorectal cancer. As in patients with this type of colorectal cancer, a high concentration of cancer-associated fibroblasts is found within the tumors of these mice.

In the current study, the researchers used these mouse models, as well as cells grown in the test tube and organoids (tiny clusters of cells grown in a dish) to further study the relationship between cancer cells and cancer-associated fibroblasts. “We found that the cancer cells send out a signal that changes the fibroblasts,” Dr. Moscat said. “The fibroblasts that emerge make the tumor more aggressive and more stealthy to the immune system.”

That molecular switch depletes levels of a protein called PKCz, which in turn increases levels of another protein called SOX2 in the fibroblasts. These changes appear to make the fibroblasts more friendly to the promotion of cancer growth.

The researchers used animal models to test the behavior of the cells they had altered in the lab. They also performed a type of analysis called single-cell RNA sequencing to further confirm that their observations in the lab matched what is observed in patients samples.

Drs. Moscat and Diaz-Meco say now that they understand the communication between cancer cells and fibroblasts, they believe that drugs could be developed to block it. “The fibroblasts are acting in a way that protects the tumor from the immune system,” Dr. Moscat said. “We want to find ways to target the fibroblasts that deprives the tumors of this protective environment.” These drugs would likely be used in combination with immunotherapy, to first lower the defenses of the fibroblasts, allowing the immune cells that are activated by checkpoint blockade drugs to better do their jobs.

“Now that we understand the roles of SOX2 and PKCz,” Dr. Diaz-Meco said, “we have two good biomarkers that we could use to assign patients to trials with these drugs.”

The researchers noted that the findings from this study could also apply to other cancers, especially pancreatic cancer. Pancreatic tumors also contain large numbers of fibroblasts that appear to make these tumors less receptive to treatment.

References: Hiroaki Kasashima, Angeles Duran, Anxo Martinez-Ordoñez, Eduard Batlle, Maria T. Diaz-Meco, Jorge Moscat, “Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population”, Developmental Cell, 2020. https://www.cell.com/developmental-cell/fulltext/S1534-5807(20)30834-0 DOI: https://doi.org/10.1016/j.devcel.2020.10.014

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Certain CBD Oils No Better Than Pure CBD At Inhibiting Certain Cancer Cell Lines (Medicine / Oncology)

Cannabidiol (CBD) oils are equally or less effective at inhibiting the growth of certain cancer cells compared to pure CBD, according to Penn State College of Medicine researchers. The results of their recent study indicate that future research into the clinical applications of cannabinoids should include an analysis of whether the pure cannabinoid compound or intact plant material is more effective at achieving the therapeutic effect.

Cannabidiol (CBD) oils are equally or less effective at inhibiting the growth of certain cancer cells compared to pure CBD, according to Penn State College of Medicine researchers. The results of their recent study indicate that future research into the clinical applications of cannabinoids should include an analysis of whether the pure cannabinoid compound or intact plant material is more effective at achieving the therapeutic effect. Image: GETTY IMAGES | MysteryShot

The researchers evaluated whether CBD oils were better than pure CBD at inhibiting the growth of different cancer cell lines. They studied brain, skin and colorectal cancers — using two cell lines for each cancer type — and found that pure CBD was able to reduce cell viability in three of the six cell lines tested and that the effect was cell line specific and not specific to select cancers. None of the CBD oils tested were able to reduce viability to a greater extent than pure CBD.

Prior research found that CBD or tetrahydrocannabinol (THC) can reduce cancer cell viability in some cancer cell models. Proponents of medical marijuana argue that there is an additive effect between the various compounds in the plant material that increases its therapeutic efficacy compared to individual, pure cannabinoid compounds. Kent Vrana, professor and chair of the Department of Pharmacology, said the study did not support this concept, known as the “entourage” effect.

“Based on our results, we recommend that specific investigations on the entourage effect be carried out when determining the therapeutic uses of medical marijuana and other cannabinoid products,” Vrana said.

Wesley Raup-Konsavage, co-author of the study published in the journal Medical Cannabis and Cannabinoids, said the study was carefully designed so that the amounts of CBD oil used for testing had an equivalent amount of CBD as the pure CBD in the experiments. The researchers obtained three types of CBD oil with certificates of analysis and had their composition verified by a third party laboratory. Equal concentrations of CBD were used to treat the six cell lines.

After evaluating the viability of the treated cell lines, researchers determined that the CBD had an effect on one of each of the colorectal cancer, melanoma and glioblastoma cell lines tested. The viability of the other cell lines tested was not significantly reduced.

Because a previous study evaluating the use of THC for treating breast cancer cells suggested that there is an entourage effect in that context, Vrana cautioned that careful testing of cannabinoids should be done for each proposed therapeutic context.

“Pure CBD had the ability to reduce certain cancer cell types’ viability in this study,” Vrana said. “It would be reckless for a consumer to assume that a CBD oil product off the shelf could have the same effects for them, which is why careful studies around the entourage effect are needed for each intended therapeutic application.”

Vrana said that even if there were cases where the entourage effect were proven for therapeutic uses, cannabinoid products are unregulated and consumers would not be able to know in many cases whether an off-the-shelf or off-the-street product had the right components to result in the desired therapeutic outcome.

“The variability in composition and activities of botanical extracts highlights difficulties in assessing their therapeutic potential compared to pure chemical compounds,” Vrana said. Raup-Konsavage and Vrana plan to continue investigating the “entourage” effect of cannabinoids in other therapeutic applications.

References: Raup-Konsavage W.M., Carkaci-Salli N., Greenland K., Gearhart R., Vrana K.E., “Cannabidiol (CBD) Oil Does Not Display an Entourage Effect in Reducing Cancer Cell Viability in vitro”, Karger, 2020. https://www.karger.com/Article/FullText/510256 Doi: https://doi.org/10.1159/000510256

Provided by Penn State College of Medicine

Giving The Immune System A Double Boost Against Cancer (Medicine)

Cancer immunotherapies, which empower patients’ immune systems to eliminate tumors, are revolutionizing cancer treatment. Many patients respond well to these treatments, sometimes experiencing long-lasting remissions. But some cancers remain difficult to treat with immunotherapy, and expanding the impact of the approach is a high priority.

A highly specialized cell, the fibroblastic reticular cell, coordinates immune responses to cancer cells. In this image, a single fibroblastic reticular cell is identified, by staining it: the cell nucleus (blue), markers that identify fibroblast cells (red), and a molecule that attracts immune cells (green). ©CSHL, 2020.

In the October 30 issue of the Proceedings of the National Academy of Sciences, a team led by Cold Spring Harbor Laboratory scientists Tobias Janowitz and Douglas Fearon together with Duncan Jodrell at the Cancer Research UK Cambridge Institute and Centre, University of Cambridge reports on a clinical trial of a drug that induces an integrated immune response in the tumors of patients with cancer types that do not usually respond to immunotherapy. The researchers hope the potential treatment might make such tumors more responsive to the class of drugs known as immune checkpoint inhibitors.

Checkpoint inhibitors release natural brakes on the immune system, freeing it to find and destroy cancer cells. But they generally have not been effective against cancer cells with low levels of genetic mutation. Janowitz said:

“Those tumors often do not seem to be visible to the immune system and do not seem to be unmasked by these therapies that are currently available. And we have reasons to believe that that is because they can engage an immune suppressive pathway that keeps most of the immune cells out of the cancer cell nest.”

In this clinical trial, the research team interrupted that immunosuppressive pathway with a drug called plerixafor. The drug was administered continuously by I.V. for one week to 24 patients with either pancreatic cancer or colorectal cancer with a low tumor mutational burden. All patients had advanced disease, and biopsies were collected from metastatic tumors before and after treatment.

When the team analyzed those patient samples, they found that critical immune cells had infiltrated the tumors during the time patients received plerixafor, including a cell type known to summon and organize key players in the anti-cancer response. The finding was encouraging because the team detected changes that have also been observed in patients whose cancers responded well to checkpoint inhibitors.

Jodrell, who led the planning and patient recruitment for the clinical study, said, “I am delighted that the work of this multi-disciplinary team has translated important laboratory findings into patients, with the potential to make a difference in these hard-to-treat cancers.” A clinical trial based on this study is about to start recruitment and will test the effects of combining plerixafor with an approved checkpoint inhibitor.

References: Daniele Biasci, Martin Smoragiewicz, Claire M. Connell et al., “CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response”, PNAS first published October 30, 2020; https://doi.org/10.1073/pnas.2013644117 link: https://www.pnas.org/content/early/2020/10/27/2013644117

Provided by Cold Spring Harbor Laboratory

Thymoquinone Induces Apoptosis & DNA Damage In 5-Fluorouracil-resistant Colorectal Cancer (Oncology / Medicine)

Volume 11, Issue 31 from @Oncotarget reported that TQ decreased the expression levels of colorectal stem cell markers CD44 and Epithelial Cell Adhesion Molecule Ep CAM and proliferation marker Ki67 in colonospheres derived from both cell lines and reduced cellular migration and invasion.

TQ induces apoptosis and reduces proliferation in NOD-SCID and NOG mice. ©Correspondence to – Hala Gali-Muhtasib – amro@aub.edu.lb and Wassim Abou-Kheir – wa12@aub.edu.lb

Altogether, the research team’s findings document TQs effect on colorectal cancer stem-like cells and provide insights into its underlying mechanism of action.

Dr. Hala Gali-Muhtasib from The Department of Biology, American University of Beirut, Lebanon and The Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Lebanon and Dr. Wassim Abou-Kheir also from The Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Lebano said, “Colorectal cancer (CRC) is the third most common cancer in both men and women and the third leading cause of cancer-related deaths in the United States.”

“Colorectal cancer (CRC) is the third most common cancer in both men and women and the third leading cause of cancer-related deaths in the United States.”

  • Dr. Hala Gali-Muhtasib, The Department of Biology, American University of Beirut & The Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut and Dr. Wassim Abou-Kheir, The Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut
    The ability of TQ to target nine of the ten hallmarks of cancer as well as its efficacy, selectivity against colorectal cancer and lack of toxicity to normal tissues makes it potentially interesting for colorectal cancer therapy.

TQs ability to inhibit colorectal cancer growth and invasion and induce cell cycle arrest and apoptosis in colorectal cancer cell culture and animal models have been documented by this Research Team and others.

In this study, the authors focused on investigating TQs efficacy on human colorectal cancer HCT116 cells, which are sensitive and resistant to 5FU. The main aim was to study the effect of TQ on targeting the self-renewal capacity of colorectal CSCs enriched from the parental and 5FU-resistant cell lines using the advanced three-dimensional culture sphere-formation and propagation assay.

In vitro and in vivo studies revealed the significant inhibitory potential of TQ on colorectal cancer cells with stem-like properties, which was found to be mainly mediated by induction of apoptosis.

This study documents TQs promising effect on CRC cancer stem-like cells both in vitro and in vivo.

The Gali-Muhtasib/Abou-Kheir Research Team concluded in their Oncotarget Research Article, “our study demonstrated that low concentrations of TQ could target CSCs enriched from 5FU-sensitive and resistant colorectal cancer HCT116 cell lines, suggesting a promising effect of TQ on chemoresistant cells. This effect, when coupled with the apoptotic effects of TQ in human CRC cultures and xenografts, indicates that this relatively non-toxic and inexpensive compound merits further clinical investigation.”

References: Ballout F., Monzer A., Fatfat M., Ouweini H. El, Jaffa M. A., Abdel-Samad R., Darwiche N., Abou-Kheir W., Gali-Muhtasib H. Thymoquinone induces apoptosis and DNA damage in 5-Fluorouracil-resistant colorectal cancer stem/progenitor cells. Oncotarget. 2020; 11: 2959-2972. Retrieved from https://www.oncotarget.com/article/27426/text/

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