NFCR Writer David Perry, Author at NFCR - Page 2 of 3

NFCR Writer David Perry

“Background Genetic Risk” Studied in Breast Cancer

From a genetic standpoint, the human body is something like a symphony, with individual genes often acting as part of a larger sum. In the case of breast cancer, it can be that no one gene is so mutated as to cause the disease. Rather, cancer results more from the combined effect of a series of genes, individual ones of which, each by itself, would be of minimal concern. This idea was long suspected in the medical community, but it was not until last year that scientists had tools to collect and analyze the thousands of genomes needed to quantify it.

“It’s like a landscape full of hills and valleys, with each risky variant like a house on top of it,” said researcher, Dr. Na Li. “If you inherit a high-risk variant — a tall house — but live in a valley, your overall risk of breast cancer may end up being average because your genetic landscape pulls it down.”

While enormous strides have been made in linking a patient’s genes to their risk for breast cancer, about half of those considered under Li’s “high-risk variant” have no known genetic cause for their condition. This suggests a more complicated explanation: That “polygenic risk,” that is, risk conferred by a combination of genetic variants, was involved.

Dr. Li and her colleagues sequenced up to 1,400 candidate breast cancer genes in 6,000 familial breast cancer patients and 6,000 cancer-free controls. In this large sample, they searched for potential cancer-associated genes suggested by the literature, collaborators and their own previous results, and identified at least 46 genes that were at least twice as likely to have mutations among participants with breast cancer than in those without.

“When you know which gene is conferring the risk of breast cancer, you can provide a more precise estimate of risk, know what to expect and watch out for, and tailor risk management strategies to the patient,” said lead researcher, Dr. Ian Campbell.

They also used the data to calculate a polygenic risk score for each patient, and combined this score with data on their high and moderate-risk variants to estimate each patient’s overall risk of developing breast cancer. In the coming years, the researchers plan to expand the study internationally to further test and refine their findings across populations. They also hope to bring these more precise risk estimates into the clinic, to more accurately reassure women about their personal risk of cancer, or — if risk is high — advise preventive strategies such as screening at a younger age.

While this study is important and insightful, one mustn’t—nor do its authors—lose sight of the impact of individual genes. Indeed, the National Foundation for Cancer Research awarded its 2016 Szent-Györgyi Prize for Progress in Cancer Research to the University of Washington’s Mary-Claire King, Ph.D., who discovered the BRCA1 gene—providing the first evidence of genetic predisposition to breast cancer. Her proof of existence of BRCA1 and the identification of its location made genetic screening for breast and ovarian cancers possible.

The research by Li and Campbell identified candidate breast cancer predisposition genes through whole exome sequencing of BRCAx families and equal numbers of cancer free women. King’s discoveries represent a fundamental step in the understanding of cancer and have changed the face of cancer prevention, screening, diagnosis and treatment. Li and Campbell’s work fine tunes this understanding of impact of individual gene’s known to be associated with higher incidences of breast cancer by too accounting for broader “background genetic risk.”   

Reference:

Li, Na, et al. The contribution of rare variants, polygenic risk, and novel candidate genes to the hereditary risk of breast cancer in a large cohort of breast cancer families. Presented at the American Society of Human Genetics 2017 Annual Meeting. Orlando, Florida. (Oct 20, 2017

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Protein Fueling Gallbladder Cancer Identified

With February being Gallbladder and Bile Duct Cancer Awareness Month, the National Foundation for Cancer Research wishes to profile a recent study focused on the indication.

Like cancers of other organs buried deep within the body, gallbladder cancer is notoriously difficult to diagnosis in its beginning stages; most patients do not even notice anything is wrong until only after their cancer has progressed into late-stage. A recent study out of Germany, however, offers hope for early detection.

Working in collaboration with pathologists at the University of Magdeburg , Dr. Sonja M. Kessler, a research pharmacist in a group led by Professor Alexandra K. Kiemer at Saarland University, has identified a new pathway that may allow improved prognosis and treatment of the disease. Kessler has discovered a protein that is linked with tumor growth and that functions as a prognostic marker, thus providing an indication of how the cancer may progress.

Kessler’s research revolves around a trio of easily identifiable proteins: IMP1, IMP2 and IMP3, which are conspicuously involved with the development of embryos. Under regular circumstances, once a child is born, these proteins then switch themselves off permanently within the child’s genetic make-up and play no further role. In the case of some cancers, however, especially gallbladder, this set of genes switches back on, much to the detriment of the individual.

“Because IMP2 promotes cell division and proliferation, it also drives the growth of tumors,” sums Kessler. “We were able to identify the proteins in a large number of tissue samples from gallbladder [cancer] patients. We were also able to show that the tumor grows faster when the cells contain larger amounts of the IMP2 protein. And in those cases, patient prognosis is poorer.”

Like many other cancers of deep-body organs, the statistics for gallbladder cancer are dim; the five-year survival rate for gallbladder cancer that has spread is 4 percent or less. However, early detection improves those number dramatically — if the cancer is discovered, has the potential to be invasive, but has not spread, (also known as “in situ” or stage 0), the survive rate rises to 80 percent. Detection at this early stage is key, as it is with any cancer. Using IMP2 as a prognostic marker would be a boon to medical science. In 2017, an estimated 4,000 persons were diagnosed with gallbladder cancers, with incidence rates 66 percent higher in women than in men.

By identifying the role of IMP2, the results of Kessler’s research may provide the basis for new effective drug treatments; research can now be undertaken to influence, slow or even completely prevent the harmful processes that are set in motion by the protein.

Kessler’s work can be found in the Oncotarget medical journal.

References:

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Cervical Cancer to “Skyrocket” Among Older Women

A study out of the United Kingdom predicts that while cervical cancer in young women is set to decline 75 percent by 2040, with deaths close to eradicated, women aged 50-64 will see a 62% rise in the disease, leading to a 143% rise in mortality, from 183 deaths in 2015 to an estimated 449 in 2040. The research was published last month in The Lancet Public Health journal.

Funded and commissioned by Jo’s Cervical Cancer Trust, the sole UK charity dedicated to women affected by cervical cancer and cervical abnormalities, a team at Queen Mary University of London established a flexible model exploring current cervical cancer rates and extending to those presumed to exist by 2040. Factors included in the study were the impact of advances in screening technology, and introducing both human papillomavirus (HPV) primary screening and the 9-valent HPV vaccine.

“This study shows how the age-specific incidence of cervical cancer will change over the next 20 years,” observes Dr. Alejandra Castanon from Queen Mary University. “Women currently aged between 25 and 40 will remain at high risk of cervical cancer throughout their lives, whilst women younger than 25 will see their risk decrease by around 50%. This has implications for the way we invest in and target screening.”

Cervical cancer is the most common cancer in women under 35 in the UK but, according to the model, this will shift dramatically by 2040 with the burden of the disease moving to older women. Among younger women, born after 1991 and who have benefited from the introduction of the HPV vaccination program in 2008, eradication of the cancer is firmly on the horizon.

The research finds that:

  • Incidence among 50-54 year olds will increase 50% (177 cases in 2015 to 265 cases in 2040)
  • Incidence among 60-64 year olds will climb 54% (144 cases in 2015 to 222 in 2040) and mortality 109% (79 to 165 deaths a year)
  • The introduction of more effective vaccination and screening test could see incidence more than halve among 25-44 year olds (1,313 cases in 2015 to 599 in 2040)
  • Screening attendance is declining year-on-year, having fallen 3.4% in England since 2012, and if it were to decline to 66% (currently 72%) among 60-64 year olds alone, incidence would rise 71% and mortality could rise 128%.

The model clearly shows how regular HPV screening is of utmost importance in reducing risk of the disease among women born before 1991. The researchers and charity warn that delays in such will only exacerbate the burden of disease among this age group. Both groups stress increasing screening coverage must remain a critical challenge and priority.

“We are faced with an aging population and risk among older women skyrocketing, therefore changes to the program which could reduce this risk must be explored, including increasing the screening age from 64 and self testing,” notes Jo’s Cervical Cancer Trust Chief Executive Robert Music. “We want to see cervical cancer become a disease of the past with no more women losing their lives to the disease.”

In the United States, as of 2017, 12,820 women will be diagnosed with cervical cancer. If found at an early stage, the 5-year survival rate for women with invasive cervical cancer is 91%. If cervical cancer has spread to immediately surrounding tissues or organs and/or the regional lymph nodes, that rate drops to 57%. If the cancer has spread to a distant part of the body, the 5-year survival rate is 17%. It is estimated that 4,210 deaths from the disease will occur this year.

References:

Castanon, Alexandra, et al.  Prediction of cervical cancer incidence in England, UK, up to 2040, under four scenarios: a modeling study. The Lancet Public Health. (December 2017) DOI: http://dx.doi.org/10.1016/S2468-2667(17)30222-0

Cervical Cancer: Statistics. Cancer.net. (July 2017). DOI: https://www.cancer.net/cancer-types/cervical-cancer/statistics

 

 

 

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New Therapeutic Option for Triple-Negative Breast Cancer

Triple-negative breast cancer, one of the deadliest and most aggressive forms of breast cancer, spreads quickly, is resistant to many chemotherapies and is likely to reoccur even after a seemingly successful round of therapies. The cause for the later is the resiliency of a subset of cancer cells called cancer stem cells. A recent development may give medical science a method of combating them.

In the Proceedings of the National Academy of Sciences, researchers from Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine showed triple-negative breast cancer cells are highly vulnerable to interferon-β, a potent antimicrobial that also activates the immune system. The new study shows interferon-β impairs breast cancer cells’ ability to migrate and form tumors. The study also suggests interferon-β treatment could improve outcomes for certain breast cancer patients.

“We demonstrate that interferon-β reverses some of the more aggressive features of triple-negative breast cancer, which are responsible for metastasis and therapy-failure,” said Mary Doherty, first author and pathology graduate student at Case Western. “The survival of cancer stem cells following therapy is believed to be responsible for therapy failure in patients. We found that evidence of interferon-β in triple-negative breast cancer tumors correlates with improved patient survival following chemotherapy.”

The new study showed interferon-β directly targets cancer stem cells. In laboratory dishes, regular treatments of interferon-β kept triple-negative breast cancer stem cells from migrating — the first step in metastasis. Even two days after stopping treatment, dishes with interferon-β added had approximately half the number of migrating stem cells as controls. Cells exposed to interferon-β also lacked markers characteristic of early tumors and failed to aggregate into tumor-like spheres.

A breast cancer tissue database was integral to the study. It was found that elevated interferon-β levels in breast tissue correlated with extended patient survival and lower cancer recurrence rates. Patients with higher interferon-β levels in their breast tissue were approximately 25 percent less likely to experience a recurrence than those with low levels. The authors concluded that interferon-β plays a “positive, critical role” in triple-negative breast cancer outcomes.

The Case Western team stressed the practical application of their findings is still in the future. The researchers are now studying how interferon-β may modulate the immune system to carry out its anti-cancer effects. They also plan to conduct clinical trials evaluating interferon-β as a new therapeutic option for triple-negative breast cancer, either alone or in combination with traditional chemotherapy. Such a study could require novel methods to deliver interferon-β to breast cancer tumors.

“Our future studies will examine improved methods of interferon-β delivery to the tumor site incorporating nanoparticle technology,” says Doherty.

References:

Dohety, Mary R., et al. Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. (November 10, 2017). Proceedings of the National Academy of Sciences of the United States of America. DOI: http://www.pnas.org/content/early/2017/12/07/1713728114.short?rss=1

 

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Genetic Breakthrough in Aggressive Prostate Cancer Research

double helix breaking through prostate cancer mazeCancer researchers at the Thomas Jefferson University in Philadelphia have zeroed in on a specific type of gene loss that sets off large-scale genetic changes that could make prostate cancer both resistant to treatment and more likely to spread. The discovery concerns the retinoblastoma (RB) susceptibility gene, the first “gatekeeper gene” discovered for cancer.

“RB loss causes a major reprogramming of gene expression, allowing induction of pathways that promote features that induce characteristics of lethal disease,” said senior author Karen Knudsen, of the Sidney Kimmel Cancer Center (SKCC) at Thomas Jefferson University.

RB is a tumor suppressor gene whose dysfunction has been found in many cancers. Under normal circumstances, this gene restricts a cancerous cell’s ability to replicate DNA by preventing its progression from the first gap phase (the first of four stages of cell division) to the synthesis phase (where DNA is replicated).

Spearheaded by first author Christopher McNair, a graduate student in the laboratory of Dr. Knudsen, the study undertook an extensive analysis of tumor samples and cell-free DNA samples from patients with advanced, lethal-stage prostate cancer. The study is the first to identify the molecular consequences of RB loss and illustrate the clinical relevance of RB-loss-induced transcriptional rewiring. Existing methods exist to experimentally remove RB in order to study it, but how that gene’s loss triggered more aggressive cancers was not understood.

It was found that complete loss, rather than inactivation, of the RB gene was associated with changes in gene-networks closely linked to the aggressive disease. Surprisingly, the cancer-promoting program that RB-loss unleashed is distinct from the cell-cycle control genes that RB is best known for controlling. Multiple clinical trials are now underway in Philadelphia that will determine the impact of RB status as a means to guide more precise cancer therapy.

“Unlike breast cancer, all prostate cancers are currently treated in an identical fashion,” said William Kevin Kelly, leader of the Prostate Cancer Program at SKCC. “This discovery, and the clinical trials we have underway, suggest that RB status might be used as means to stratify patients into more effective treatment regimens.”

Reference:

McNair, C., et al. Differential impact of RB status on E2F1 reprogramming in human cancer. Journal of Clinical Investigation. Dec. 2017. https://www.jci.org/articles/view/93566

 

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Hypertension Medicine Linked to Skin Cancer

A research study conducted in both Denmark and the United States found a strong link between skin and lip cancer rates and the use of hydrochlorothiazide, one of the most popular blood pressure medicines in the world. The team, composed of members of the University of Southern Denmark, the Danish Cancer Society, and Dr. Armand B. Cognetta, Jr. of Florida State University, concluded the risk of developing skin cancer, squamous cell carcinoma and basal cell carcinoma in particular, is up to seven times greater for users of medicine containing hydrochlorothiazide.

“We knew that hydrochlorothiazide made the skin more vulnerable to damage from the sun’s UV rays, but what is new and also surprising is that long-term use of this blood pressure medicine leads to such a significant increase in the risk of skin cancer,” says Anton Pottegård, Associate Professor at the University of Southern Denmark and the initiator of the study.

“We have seen and followed many patients with different skin cancers where the only risk factor apart from exposure to sunlight seems to be hydrochlorothiazide,” echoes Cognetta, who has empirically noted in the past that hydrochlorothiazide is suspiciously prevalent among his patients, several of whom have hundreds of skin cancers each.

The study is based on about 80,000 Danish cases of skin cancer, and researchers calculated that about 10 percent of all Danish cases of squamous cell carcinoma may be caused by hydrochlorothiazide, a frequently used drug to treat hypertension in combination with other antihypertensive medicines. Researchers are quick to point out that in an industry where several drugs have similar sounding names, only medicines containing hydrochlorothiazide have been found to increase the risk of cancer. Other drugs may contain “hydrochlor” in their scientific name, but they are not chemically related to hydrochlorothiazide and therefore do not increase the risk of skin cancer per this study.

It has long been known that ultraviolet (UV) radiation can cause cancer, but the idea that hydrochlorothiazide could directly increase the chances of cancer, although suspected, remained elusive and unproven. Cognetta, who operates in sunny Florida, welcomes the study results, which establishes a link.

Developments in the field of skin cancer too include work by NFCR-sponsored scientist, Dr. James Basilion. He and his team at Case Western Reserve University are exploring how to make the surgical removal of skin cancer a more effective procedure. An imaging technique which they have designed and are perfecting can better allow surgeons to assess—during surgery and in real time—if all cancer cells have been removed. This novel approach could dramatically reduce re-excision rates and reduce or eliminate local tumor recurrence.

References:

Pottegård, Anton, et al. Hydrochlorothiazide use and risk of non-melanoma skin cancer: A nationwide case-control study from Denmark Journal of the American Academy of Dermatology. Dec., 2017 http://www.jaad.org/article/S0190-9622(17)32741-X/pdf.

 

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Hormone Receptor Identified for Aggressive Breast Cancer

breast cancer tumorTriple-negative breast cancer (TNBC), which comprises 15% of diagnosed breast cancers, is an aggressive oncology type defined by the absence of specific receptor proteins that bind the estrogen and progesterone hormones present on normal breast cells. While advances have been made in TNBC therapies, because this particular type of cancer can so quickly spread to other organs, the long-term survival rate remains low. However, a study done by the Mayo Clinic identifies a hormone receptor which offers hopes for an enhanced treatment option.

The research, published in the October issue of Oncotarget, found the growth of TNBC cells that lacked estrogen receptor alpha, ERα, could be significantly slowed by treatment with estrogen or estrogen-like chemicals if the cells presented a second receptor, ERβ, short for estrogen receptor beta. The Mayo team also tested this approach in a mouse model which had TNBC cells grafted to it, and found that estrogen could prevent tumor growth and in some cases even cause tumor regression, if the cells expressed ERβ.

Importantly, further analysis found that the effects of estrogen on ERβ were in part due to proteins called cyclin-dependent kinases (CDKs) that control when and how cells divide, a vital cog in the mechanics of cancer.

Triple negative breast cancer typically occurs in young, pre-menopausal women, and is more prevalent in women of African-American descent. Women diagnosed with TNBC usually present with larger tumors of higher grade that have spread to the lymph nodes. Despite current treatment strategies, chemotherapy and radiation therapy, 34% of patients with newly diagnosed TNBC develop recurrent disease within five years of diagnosis following aggressive chemotherapy treatment.

“Our data suggests that the tumor-suppressive effects of ERβ in triple negative breast cancer are partly controlled by cell cycle regulating proteins suggesting that targeting these proteins may lead to potentially new and effective therapies for triple negative breast cancer,” said team member Dr. John Hawse.

The researchers also note that other studies have observed that patients with TNBC who lack ERα, but have ERβ, have not only an increased survival rate but are also more likely to become cancer-free, supporting the notion that drugs designed specifically to activate ERβ may provide therapeutic benefits in these patients.

Hawse and others in the study stress these findings are preliminary, and will have to be evaluated further in cellular and animal models before they can be considered for a clinical trial, a task that the research team is expected to take on in future studies.

Another promising research avenue on the horizon for TNBC treatment is being conducted by a collaborative team of NFCR-sponsored scientists: molecular pharmacologist Dr. Susan Band Horwitz of Albert Einstein College of Medicine and organic chemist Dr. Amos. B. Smith, III, of the University of Pennsylvania. Dr. Smith is synthesizing analogues of discodermolide, a natural product from a deep-water Caribbean sponge. Dr. Horwitz has demonstrated the leading candidates show major anti-tumor effects in TNBC cell lines and complex tumor models. Their years-long research on selected discodermolide analogues can have a high impact on the treatment of recalcitrant TNBC and ovarian and lung cancers as a first line drug for patients, and importantly, for patients whose cancer has spread or metastasized to other vital organs.

Reference:

Reese, Jordan M., et al. “ERβ inhibits cyclin dependent kinases 1 and 7 in triple negative breast cancer,” Ocotarget (Oct. 2017).

 

 

 

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Forty Percent of American Cancer Cases Linked to Weight

In a report published by the U.S. Centers for Disease Control and Prevention, obesity and even being overweight are associated with at least 13 different types of cancer, comprising 40% of all cancer diagnoses. More than 630,000 people in the U.S. are annually diagnosed with a cancer associated with obesity and high weight.

“Around 55 percent of cancers in women and 24 percent of cancers in men were associated with overweight and obesity,” said Dr. Lisa Richardson, director of the CDC Division of Cancer Prevention and Control.

The 13 cancers are meningioma (cancer of the tissue covering the brain and spinal cord), thyroid and multiple myeloma (cancer of the blood cells), adenocarcinoma (esophagus), colorectal cancer, and cancers of the kidneys, uterus, ovaries, breast (post-menopausal), gallbladder, upper stomach, liver, and pancreas. In the period spanning 2005 to 2014, 12 of the cancers associated with weight rose seven percent, while rates of other cancers in the same period actually fell by 13%.

Also noted was the fact that most Americans do not know of the link between cancer and weight.

“Awareness of some cancers being associated with obesity and [being] overweight is not yet widespread,” said Dr. Anne Schuchat, the deputy director of the CDC.

And despite advances in colorectal cancer screenings and successful treatment, people who are overweight or obese are also about 30 percent more likely to develop that particular cancer than individuals with normal weight, according to the report. Women who are overweight or obese are about two to four times more likely to develop endometrial cancer, said Richardson.

“The obesity epidemic is a complex and major public health challenge that requires comprehensive efforts,” said Schuchat. “People can eat healthy, be physically active, and get recommended cancer screening.”

Not unsurprisingly, age is also a factor, with an uptick in the mentioned cancers occurring in people aged 50 to 74.

References:

Anne Schuchat and Lisa Richardson, “Obesity and Cancer,” Vital Signs – October Teleconference Transcript, Oct. 3, 2017.

Cancer and Obesity, Oct. 3. Date accessed: Nov. 29. https://www.cdc.gov/vitalsigns/obesity-cancer/index.html

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Lung Cancers Can Differ by Race

According to Clinical Cancer Research, a journal of the American Association for Cancer Research, recently discovered genetic differences in non-small cell lung cancers (NSCLCs) between some African-Americans and European-Americans suggest that there are racial differences in the biology of the disease. These findings could have a clinical impact on personalized cancer therapies in the future.

“We are entering the age of ‘precision medicine’ in which diagnosis and therapy decisions for each cancer patient will be based on detailed molecular and chemical fingerprints,” said researcher Bríd M. Ryan, a researcher at the National Cancer Institute’s Center for Cancer Research and the study’s author.

“Much of the revolutionary work that underpins precision medicine has been conducted on populations of European descent, with limited work in minority populations,” she added. “We want to make sure that all populations can benefit from this approach. Studying the biology of lung cancer in African-Americans is one step toward that goal.”

Dr. Ryan and her team analyzed normal and NSCLC tissue obtained from 64 African-Americans and 74 European-Americans. Tissue from 22 African-Americans and 19 European-Americans was analyzed for mRNA expression, which provides information about gene expression, and tissue from the remaining patients was analyzed for microRNA expression. These two different kinds of RNA have related, but different, roles inside the cell.

The researchers found that expression of 2,210 genes was more than two-fold increased or decreased in NSCLC from African-Americans compared with matched normal tissue. For European-American samples, 2,921 genes were differentially expressed by more than two-fold. Many of the genes were differentially expressed between NSCLC and normal tissue in both African-Americans and European-Americans, but 637 and 1,844 were differentially expressed only in African-Americans and European-Americans, respectively.

The genes differentially expressed only in the African-American NSCLC samples were enriched for those involved in stem cell biology and invasive behavior. The genes differentially expressed only in European-Americans were enriched for those involved in cell cycle, mitosis, and proliferation.

In addition, the genes differentially expressed only in African-Americans or European-Americans were analyzed using a drug-response prediction model. The two gene subsets predicted similar resistance/sensitivity for NSCLC from African-Americans and European-Americans to some drugs. For other drugs, the predictions varied by race, with NSCLC from African-Americans predicted to be resistant to 53 drugs to which NSCLC from European-Americans was sensitive. Among these drugs was irinotecan, used for treating certain types of cancer.

“This study helps close a gap in our knowledge of which genes are expressed in lung cancers from African-Americans, revealing clear differences in lung cancer biology between African- Americans and European-Americans,” said Mitchell. “By understanding these racial differences in gene expression, we can account for how they may contribute to disease progression and treatment response and, ultimately, help reduce some health outcome disparities.”

The study parallels a recent publication in Theranostics, one of whose authors is NFCR-sponsored scientist, Dr. Wei Zhang, of Wake Forest Baptist Medical Center. That team’s precision oncology study of racial differences in genetic alterations in smoking-related cancers revealed that African-Americans had a significantly increased mutation rate in the TP53 gene (tumor suppressor gene), and five genes were significantly amplified in this population. The researchers also found that a number of genes—including those that repair DNA damage—mutated at higher frequencies in African-American cancer patients versus European-Americans. 

Dr. Zhang stated, “These results provide strong evidence that genomic instability is a fundamental hallmark of cancer, and the events underlying the regulation of genome stability are centered on interactions with environmental factors and lifestyle, such as smoking.”

Too, the study points to genetic mutations common to African-Americans as a factor contributing to cancer outcome disparities. This latter discovery may lead to the development of novel diagnostic and improved therapeutic options for patients. 

References

Kytola V, Topaloglu U, Miller LD, Bitting RL, Goodman MM, D`Agostino RB Jr, Desnoyers RJ, Albright C, Yacoub G, Qasem SA, DeYoung B, Thorsson V, Shmulevich I, Yang M, Shcherban A, Pagni M, Liu L, Nykter M, Chen K, Hawkins GA, Grant SC, Petty WJ, Alistar AT, Levine EA, Staren ED, Langefeld CD, Miller V, Singal G, Petro RM, Robinson M, Blackstock W, Powell BL, Wagner LI, Foley KL, Abraham E, Pasche B, Zhang W. Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center, Theranostics. 2017; 7(11):2914-2923. doi:10.7150/thno.20355

Ryan, Bríd  M. Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans, Clinical Cancer Research. (December 2017).

 

 

 

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Using Cancer to Fight Cancer

Researchers at the University of Michigan (U-M) devised a process to grow a series of honeycomb-like arrays of tiny, lab-grown cancers that could one day help doctors zero in on individualized treatments for ovarian cancer. The findings are detailed in a study in the journal, Clinical Cancer Research.

Led by Geeta Mehta, the Dow Corning Assistant Professor of Materials Science and Engineering at U-M and head of the research team that developed the technique, the process involves growing hundreds of cultured cell masses, called spheroids, from just a few tumor cells derived from a patient. Grown in a structure called a 384-hanging drop array, each spheroid is encased in a tiny droplet of a special culturing medium. This 3-D method yields cells that grow and multiply as they would inside the human body.

The researchers hope those spheroids can serve as a testing ground unique to each patient, and lead to personalized therapies. Doctors could quickly try out many different medications, finding the best combination for an individual patient and making adjustments as the disease evolves.

The hanging drop array’s hundreds of individual compartments make it possible to grow many spheroids at once and quickly gather data about multiple drugs. This is key, as chemotherapy treatment often requires complex cocktails of multiple drugs administered together. The cells could provide a way to test many such cocktails simultaneously.

“Today we’re limited to two-dimensional cells grown in bovine serum that’s derived from cows. Cells grown this way often don’t respond to medication the same way as ovarian cancer cells inside the body,” explains Mehta. “Three-dimensional cultured spheroids provide a much more predictive way to test many different medications, and a way to grow many cultured cells from just a few of the patient-derived cells.”

A particularly pernicious cancer type, ovarian cancer’s deadly adaptability contributes to a 70% relapse rate among patients who had surgery to remove a tumor. Its free-floating spheroids shuttle cancer through the abdomen with the ability to form new tumors wherever they go—the liver, the intestines, the abdominal wall, etc. And the cells within those spheroids mutate often and unpredictably, quickly developing new strains that resist chemotherapy drugs.

“This is a really important step to expedite personalized medicine for cancer patients,” added Ronald Buckanovich, a professor of medicine at the University of Pittsburgh and a senior co-author of the study. “The ability to take patients’ samples, rapidly grow them in a more physiologic manner and study their response to therapy, without using mice, will be a faster, cheaper and more humane way to rapidly test a patient’s response to dozens of therapeutics.”

The National Foundation for Cancer Research (NFCR) too sponsors personalized medicine-based research and clinical initiatives for various cancer types. For example, Massachusetts General Hospital’s Dr. Alice Shaw focuses on targeted therapy and drug resistance in lung cancer and uses patient-derived lung cancer models to test for effective treatments. Dr. Wei Zhang of Wake Forest University’s School of Medicine utilizes data from next-generation sequencing of tumor DNA found in patients’ bloodstream to identify growth-promoting genes or drug resistant genes for guiding therapeutic approaches for breast, prostate, lung, colorectal, pancreatic and brain cancer. And Dr. Rakesh Jain, also of Massachusetts General Hospital, has been identifying molecular characteristics that cause resistance to anti-angiogenic therapy in patients with the deadliest form of brain cancer, glioblastoma multiforme (GBM); his research may allow oncologists to tailor anti-angiogenesis therapies for each patient.

Reference:

Mehta, Geeta. (2017, November) Personalized medicine-based approach to model patterns of chemoresistance and tumor recurrence using ovarian cancer stem cell spheroids. Clinical Cancer Research, pp. 22-23.

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