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Lung cancer drug could be repurposed to target ‘zombie’ proteins linked to leukemia

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A new study by scientists at the University of Liverpool highlights how a clinically-approved lung cancer drug could potentially be ‘repurposed’ to design new treatments for future cancer therapies.

The research, published in Science Signaling, focuses on a protein called TRIB2, which is linked to promoting survival and drug resistance in solid tumours and blood cancers and is therefore of particular interest as a therapeutic target.

The study was led by Professor Pat Eyers and colleagues in the Department of Biochemistry at the University’s Institute of Integrative Biology, where BBSRC Doctoral Training Programme student Dan Foulkes worked in collaboration with scientists at the Universities of Georgia and North Carolina, Chapel Hill, in the USA.

TRIB2 is part of the Tribbles (TRIB) family of pseudokinase proteins—sometimes described as ‘zombie’ enzymes, due to their inability to catalyse chemical reactions. Tribbles were named after the small, round, fictional organisms from Star Trek, whose major role in life is to eat and reproduce. Consistently, Tribble proteins play many diverse roles in cell signalling, development and cancer.

In particular, TRIB2 proteins have the ability to promote cell survival, a hallmark of cancer cells, and TRIB2 is a potential new drug target for acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), which are both in urgent need of targeted therapeutics.

Using a biochemical drug repurposing approach, the researchers discovered that a family of drugs currently approved to treat lung cancer can also degrade TRIB2 at higher concentrations in human acute myeloid leukaemia (AML) cancer cells in vitro, leading to cancer cell death.

This family of drugs, called protein kinase inhibitors, were originally designed to block a different protein called Epidermal Growth Factor Receptor (EGFR) from working in lung cancer cells, where it can help stop or slow tumour growth in some patient populations.

The approved lung cancer drug afatinib is one of a number of EGFR inhibitor compounds identified by the study as a potential drug lead for the development of TRIB2-targeted cancer therapies.

Professor Eyers commented: “A long-standing goal in cancer research is drug-induced degradation of oncogenic proteins. Our study highlights how information obtained with ‘off-target’ effects of known drugs is potentially useful because it might be exploited in the future to help eliminate a protein that is involved in a completely different type of cancer.”

The research is one of two studies featured in the latest issue of Science Signaling that explores the structures and protein interactions of TRIB pseudokinases, a focus of work in Professor Eyers’ laboratory.

More information: “Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells,” Science Signaling (2018). stke.sciencemag.org/lookup/doi … 26/scisignal.aat7951

Provided by: University of Liverpool

 

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Cancer stem cells use ‘normal’ genes in abnormal ways

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CDK1 is a “normal” protein—its presence drives cells through the cycle of replication. And MHC Class I molecules are “normal” as well—they present bits of proteins on the surfaces of cells for examination by the immune system. But a University of Colorado Cancer Center study published in the journal Cancer Research shows that a population of cancer cells marked by MHC Class I molecules and high CDK1 is anything but normal. In fact, these MHC Class I-high, CDK1 high molecules may be at the heart of conditions including melanoma, pancreatic and colon cancers.

 

These cells may, in fact, be the long-sought cancer stem cells that often resist treatments like chemotherapy to reseed these cancers once treatment ends.

From the outset, the goal of this study was different than most. Often, cancer researchers will grow tumors and then ask what kinds of drugs or genetic changes make tumors grow or shrink. However, the current study wondered not what makes tumors change size, but what factors in these cells initiate tumor growth in the first place. To answer this question, the study used patient samples, mouse models and publicly available genetic data to search for the genetic/genomic commonalities in cells capable of initiating melanoma, pancreatic and colon cancers.

The findings start with a molecule called MHC Class I, a common molecule that coats the outside of human cells and functions a bit like a hand waving a flag. When MHC Class I molecules wave “flags” (actually bits of proteins), that are not from host tissue, the immune system recognizes the cell as foreign and attacks it. For this reason, most cancer cells downregulate MHC as a way of evading the immune system.

But the current study shows that the population of cancer cells able to initiate the formation of new tumors does not downregulate MHC Class I molecules. In fact, if anything this special population of cancer cells upregulates MHC Class I molecules.

“Probably, these cells have another way to evade the immune system,” says Mayumi Fujita, MD, Ph.D., investigator at CU Cancer Center and professor in the CU School of Medicine Departments of Dermatology and Immunology/Microbiology.

Oddly, this population of cancer cells that retains MHC Class I molecules also retains another feature of healthy cells, namely the presence of a protein called CDK1. CDK1 is a master regulator of the cell cycle—with CDK1, cells progress through the cycle of replication; without CDK1, they do not. In this case, the more CDK1, the more able melanoma cells were to initiate new tumors.

“Our next question was why,” Fujita says. “Why would CDK1 control not just the cell cycle, but also stem-ness?”

Finally, the answer includes something that is not “normal.” Sox2 is a transcription factor that helps embryonic and neural stem cells keep their stem-ness. It is also a known marker of cancer stem cells, implicated in the development of more than 25 forms of the disease. Despite its identification as a driver of cancer, Sox2 remains a difficult target.

“It’s very difficult to control a transcription factor like Sox2. We can show Sox2 is very important for tumorigenesis, but it’s difficult to have a Sox2 inhibitor,” Fujita says.

However, the current study found that CDK1 directly interacted with Sox2 to keep these cancer cells “stemmy.” And here is the important part: “If CDK1 controls Sox2 function through this interaction, probably we can someday inhibit it, maybe through some way of targeting CDK1 or perhaps some way to interfere with the interaction of CDK1 with Sox2,” Fujita says.

Importantly, this signature of MHC Class 1, CDK1 and Sox2 was common across melanoma, colon and pancreatic cancers, implying that cancer stem cells across cancer types may share common features.

“We can’t say that all tumor types have this signature, but it’s prevalent. We think probably this phenotype is very common in melanoma, pancreatic and colon cancer,” Fujita says.

Moving forward, the Fujita group hopes to further define the mechanism of Sox2 regulation via CDK1 in hopes of finding essential links that might be targets for new drugs aimed, eventually, at stopping the action of Sox2.

More information: Dinoop Ravindran Menon et al, CDK1 interacts with Sox2 and promotes tumor initiation in human melanoma, Cancer Research (2018). DOI: 10.1158/0008-5472.CAN-18-0330

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A protein called vaccinia-related kinase 1 may help cancer establish itself in new areas of the body during metastasis

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When mammary epithelial cells are grown in a 3D culture matrix, they proliferate and form hollow colonies that mimic the organization of an epithelial tissue. 3D cultures of control cells (left) and cells that over-express VRK1 (right) behave very differently in this context. Although all cells organize into colonies and form cell:cell junction markers (red, cadherin), VRK1 over-expression leads to much more vigorous cell proliferation and the formation of larger colonies. These results may have relevance to the colonization of tissues during cancer metastases. (images taken from Mon, MacKinnon and Traktman, PLoS One) Credit: Created by Paula Traktman from images appearing in Figure 5C of the September 4, 2018 article by Mon, MacKinnon and Traktman, as allowed by the Creative Commons License, creativecommons.org/licenses/by/4.0/
Sometimes negative results can point researchers in the right direction.

In results published in PLOS ONE on September 4, 2018, scientists at the Medical University of South Carolina (MUSC) examined a protein called vaccinia-related kinase 1 (VRK1) that they hypothesized was important for metastasis. They found that, rather than causing cancer cells to migrate and invade, VRK1 over-expression had the opposite effect.

Yet this behavior could well help cancer to establish itself in new parts of the body, according to study director and Hirschmann Endowed Professor Paula Traktman, Ph.D., in the MUSC Hollings Cancer Center.

Traktman and graduate student Aye M. Mon started with the idea that high levels of VRK1 might be associated with breast cancer. Other research had suggested this, and Traktman’s own work had revealed that depleting VRK1 caused cells to grow more slowly and to cause smaller tumors and fewer metastases in mice. Drawing on these results, Mon and Traktman wanted to see how cells would grow when VRK1 was over-expressed. “The logic was that, if we over-express VRK1, maybe the cells would grow faster and maybe they would be invasive and migratory and contribute to metastasis,” said Traktman.

To their surprise, they found that the opposite was true. When they over-expressed VRK1 in mammary epithelial cells growing in tissue culture dishes, those cells did not grow more rapidly than cells with normal levels of VRK1. And, contrary to their hypothesis, the cells tended to migrate and invade much more slowly. But, when the VRK1 over-expressors were cultured under 3-D conditions that mimic tissues, they grew more rapidly and established larger colonies. Intrigued, Mon and Traktman took a closer look at the characteristics of these cells. They examined a hallmark of cancer cells known as epithelial-to-mesenchymal transition, or EMT. Many cells undergo EMT on their way to becoming cancer cells. The transition enables them to migrate away from the tumor.

They observed that the cells with high levels of VRK1 were more apt to form cell-to-cell connections and had lower levels of mesenchymal markers that are often present in cancer cells. Rather, the cells seemed to undergo the opposite transition, from mesenchymal to epithelial. The cells were much less likely to migrate.

These negative results pointed the researchers in a new direction. If high levels of VRK1 caused cancer cells to migrate more slowly, perhaps VRK1 was necessary to enable cells to colonize a new area of the body. In such a process, cancer cells spreading throughout the body would need to abandon the characteristics that make them spread and adopt the traits of cells that would anchor them in place. It is that kind of behavior that allows metastases to begin growing in other parts of the body.

To confirm their new hypothesis, Traktman and Mon teamed up with pathologist A. C. McKinnon at the Medical College of Wisconsin. McKinnon provided the team with cells from breast cancer patients who had metastases to their lymph nodes. They found much higher levels of VRK1 in the lymph node metastases than in the primary tumor cells. In addition, they examined the expression levels of VRK1 in public databases of breast cancer and found that high levels of VRK1 were associated with the most aggressive cancers. Such high levels were also associated with the worst prognoses in patients with metastatic breast cancer.

Traktman summarizes the process. “For a tumor to be aggressive, some of the cells have to break off of the primary tumor and invade through the surface and into the bloodstream and then out of the bloodstream and find a new site,” said Traktman. “In order to form a metastasis in a new area, the cells have to stop being wanderers and colonize.” And it is possible that VRK1 over-expression enables such cancer cells to colonize new sites in the body.

Traktman and Mon suspect that this finding may extend to other types of cancer, such as brain cancer and liver cancer. In fact, high levels of VRK1 are found in certain types of liver cancer. These results justify the search for small molecules that might inhibit VRK1. Also, VRK1 may one day serve as a biomarker of aggressive cancers, which could thus inform oncologists as they decide on more advanced or conservative courses of treatment.

Traktman and Mon stress the importance of keeping their minds open as they conduct their research. “You can go into research with one model and be completely wrong, and it can actually turn out more interesting than you think,” said Traktman. “It’s a lesson for letting the data take you down the road to an interesting finding.”

More information: Aye M. Mon et al, Overexpression of the VRK1 kinase, which is associated with breast cancer, induces a mesenchymal to epithelial transition in mammary epithelial cells, PLOS ONE (2018).DOI: 10.1371/journal.pone.0203397

Provided by: Medical University of South Carolina

 

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Combo therapy of prostatectomy plus radiotherapy may improve survival in prostate cancer

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High-risk prostate cancer, that which has continued to grow but not yet metastasized, is commonly treated with combination therapies. Each method has pros and cons, but there is little clarity whether one might be more effective than the other. For the first time, researchers have shown that more patients live longer if treated with the combination of prostate removal plus radiation therapy. The research was published September 25th in the journal Cancer.

“There’s a lot of debate about whether to remove the whole prostate and follow up with radiation therapy. Or, as a second option, to spare the prostate and treat it using radiation therapy plus hormone-blocking therapy,” said senior author Grace Lu-Yao, Ph.D., Associate Director of Population Science at the Sidney Kimmel Cancer Center—Jefferson Health, one of only eight NCI-designated cancer centers nationwide with a prostate cancer program of excellence. “Our study suggests that removing the prostate followed by adjuvant radiotherapy is associated with greater overall survival in men with prostate cancer.”

The risks of prostate removal, or prostatectomy, are well known and include higher chance of developing incontinence and erectile dysfunction. There are some risks associated with radiation treatment and hormone therapy, but they are less common, and are typically thought to have a lower impact on quality of life. “Prostatectomy is an unpopular treatment,” said Lu-Yao. “Our study showed that only six percent of men with high-risk cancer were treated with it.” It’s not just the risk of side effects.For some men, especially those who are not fit enough for the surgery, prostatectomy is not an option. However, this may be an option for some patients to reconsider.”

In the largest population-based retrospective study to date, Dr. Lu-Yao and colleagues examined the records of 13,856 men in the Medicare-SEER registry diagnosed with locally advanced prostate cancer—cancer growth that had not yet metastasized to distant sites in the body. Dr. Lu-Yao and colleagues looked at the patients who were treated either with prostatectomy plus adjuvant radiation as one group, and compared them to another group who were treated with radiation therapy plus hormone-blocking therapy. They matched the comparison groups by age, race and co-morbidity to control for factors that may influence patient outcomes, and analyzed which group did better 10 to 15 years after their procedures.

They found that 10 years after treatment, 89 percent of the prostate removal plus radiation group was still alive. That compared with the 74 percent survival at ten years in the group that received only radiation plus hormone therapy, amounting to a 15 percent survival advantage in the group that was treated with prostate removal.

“For high-risk prostate patients we started the use of aggressive radiation therapy after surgery 20 years ago,” said Adam Dicker, Senior Vice President and Chair of the Department of Enterprise Radiation Oncology at Jefferson Health, who was not involved in the study. “We recognized that it may have curative potential.”

“However, the proportion of men undergoing prostatectomy plus radiation therapy decreased significantly over time and there were trade-offs for the survival advantages,” said Dr. Lu-Yao. Men who received the combination of surgery and radiotherapy had higher rates of erectile dysfunction (28 percent vs 20 percent) and higher rates of urinary incontinence (49 percent vs 19 percent).

Another interesting finding from the research was that slightly more than half of men diagnosed with the disease did not receive combination therapies for their prostate cancer. “Two modes of treatment are recommended by both United States and European guidelines for cancer treatment. It was surprising to see only 29 percent of patients received the recommended combination therapies, and as many as 20 percent are not getting any treatment six months after their diagnosis,” said Dr. Lu-Yao. “Our data can’t tell us the reason for this deviation from guidelines and further studies are needed.”

“One of the strengths of retrospective studies of patient data is that it reveals what happens in the real world, rather than the carefully controlled context of a clinical trial,” said Dr. Lu-Yao. “Our data is revealing the real-world practice as well as some of the advantages and disadvantages of those medical preferences.”

“This important study demonstrates that many men with high-risk prostate cancer derive a survival advantage through a multi-modality approach to their disease. Several large clinical trials are nearing completion that should validate these retrospective findings of the benefits of primary radical prostatectomy followed by additional therapies such as adjuvant radiation,” said Leonard Gomella, Chair of the Department of Urology at Jefferson (Philadelphia University + Thomas Jefferson University), who was not involved in this research.

 

More information: Thomas L. Jang, Neal Patel, Izak Faiena, Kushan Radadia, Dirk F. Moore, Sammy E. Elsamra, Eric A. Singer, Mark N. Stein, James A. Eastham, Peter T. Scardino, Yong Lin, Isaac Y. Kim, Grace L. Lu-Yao, “Comparative effectiveness of radical prostatectomy with adjuvant radiotherapy versus radiotherapy plus androgen deprivation therapy for men with advanced prostate cancer,” CancerDOI: 10.1002/cncr.31726, 2018

Provided by: Thomas Jefferson University

 

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