Tag: Cancer

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EXISTING DRUG MAY HELP TO TREAT AGGRESSIVE BRAIN CANCER

by Maria Cohut

https://www.medicalnewstoday.com/articles/322427.php

https://www.medicalnewstoday.com/authors/maria-cohut

View all articles written by Maria Cohut

Glioblastoma is an aggressive brain cancer that progresses very rapidly and often becomes treatment resistant. The commonest chemotherapy drug used to treat glioblastoma, temozolomide, tends not to be as effective as one might hope. But could a common altitude sickness drug enhance its success?

https://www.medicalnewstoday.com/articles/322427.php

To enhance the effectiveness of chemotherapy against glioblastoma, scientists turn to an unlikely aid: an altitude sickness drug.

 https://www.ncbi.nlm.nih.gov/pubmed/22122467

Temozolomide (TMZ) works by modifying DNA, so that certain proteins that allow the tumors to grow and expand do not express.

But, some tumor cells are able to “resist” TMZ’s action.

This means that the drug’s effectiveness is often limited, which affects patient survival rates.

But a new study conducted by researchers from the University of Chicago in Illinois has made an intriguing discovery.

https://pubchem.ncbi.nlm.nih.gov/compound/acetazolamide

Acetazolamide (brand name Diamox) — a drug commonly used to treat altitude sickness and other health problems, such as glaucoma and even seizures — may counteract the resistance put up by glioblastoma cells, thus enhancing TMZ’s effect.

Study director Dr. Bahktiar Yamini explains that, if the new findings hold strong, acetazolamide would be a very convenient therapeutic aid, since it is “cheap to make, easy to take, and has limited side effects.”

The researchers’ results have now been published in the journal Science Translational Medicine.

Hope for a combination treatment

The research team found that patients with this aggressive form of brain cancer tended to be TMZ treatment resistant if they had high levels of B cell CLL/lymphoma 3 (BCL-3), a protein able to counteract the action of the chemotherapy drug.

BCL-3 blocks TMZ by activating carbonic anhydrase II, an enzyme that shields the tumor cells, and allows them to continue their cycle. HYPERLINK https://www.medicalnewstoday.com/articles/322410.php?iacp

“‘Backpacked drugs’ can boost immunotherapy for solid tumors”

Working with a mouse model of glioblastoma, the team experimented with acetazolamide, testing to see whether it, in turn, would block the activity of carbonic anhydrase, thereby allowing TMZ to do its work.

“We tested this combination treatment strategy in several animal models,” explains Dr. Yamini.

This strategy, the researchers found, cured some of the mice, while other animals saw a 30–40 percent increase in survival time following the combination treatment.

That is because acetazolamide is, in fact, a carbonic anhydrase inhibitor, and the team was able to gauge this by looking, initially, at existing studies looking at human patients with glioblastoma.

In their preliminary research, Dr. Yamini and team found that individuals with lower BCL-3 levels also had longer survival rates after treatment with TMZ, compared with other patients with high levels of this protein.

“An important feature of predictors like BCL-3 is that they are informative,” explain the researchers. “They can identify pathways to improve treatment response.”

So, by looking at BCL-3 mechanisms, the scientists were eventually able to pinpoint acetazolamide as a carbonic anhydrase inhibitor that could support the effect of TMZ.

“Our data,” add the authors, show that it is the “induction of [carbonic anhydrase II] by TMZ that is important in modulating response to therapy.”

Dr. Yamini and colleagues suggest that, in the future, a prospective randomized clinical trial should be conducted in order to confirm that testing for BCL-3 can indicate which patients will respond best to TMZ, and which are likely to be treatment resistant.

The researchers hope that a combination of TMZ and acetazolamide could eventually be used to enhance treatment efficacy for patients with high levels of BCL-3. The team is already planning clinical trials and looking to recruit participants.

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RESEARCH TEAM DISCOVERS DRUG COMPOUND THAT STOPS CANCER CELLS FROM SPREADING

June 22, 2018, Oregon Health & Science University

https://medicalxpress.com/news/2018-06-team-drug-compound-cancer-cells.html

Fighting cancer means killing cancer cells. However, oncologists know that it’s also important to halt the movement of cancer cells before they spread throughout the body. New research, published today in the journal Nature Communications, shows that it may be possible to freeze cancer cells and kill them where they stand.

Raymond Bergan, M.D., Division Chief of Hematology and Medical Oncology and professor of medicine at OHSU, says that the majority of cancer treatment therapies today are directed toward killing cancer. To date, he says, no one has developed a therapy that can stop cancer cells from moving around the body.

“For the vast majority of cancer—breast, prostate, lung, colon, and others—if it is detected early when it is a little lump in that organ and it has not spread, you will live. And generally, if you find it late, after it has spread throughout your body, you will die,” says Bergan, also the associate director of medical oncology in the OHSU Knight Cancer Institute and director of the OHSU Bergan Basic Research Laboratory. “Movement is key: the difference is black and white, night and day. If cancer cells spread throughout your body, they will take your life. We can treat it, but it will take your life.”

For that reason, the study of cancer cell movement, or motility, has been the focus of his group’s research for several decades.

Stopping cancer cell movement

In 2011, Bergan and team took a novel approach to their research by working with chemists to jointly discover a drug that will inhibit the movement of cancer cells. The Nature Communications paper outlines the multidisciplinary team’s work with KBU2046, a compound that was found to inhibit cell motility in four different human cell models of solid cancer types: breast, prostate, colon and lung cancers.

“We used chemistry to probe biology to give us a perfect drug that would only inhibit the movement of cancer cells and wouldn’t do anything else,” Bergan says. “That basic change in logic lead us to do everything we did.”

A multidisciplinary team

The team of investigators includes Bergan’s team at OHSU, a chemist from Northwestern University as well as researchers from Xiamen University in China, the University of Chicago, and the University of Washington. Ryan Gordon, Ph.D., research assistant professor in the OHSU School of Medicine and co-director of the Bergan lab, says drawing upon the strengths of this cross-functional group was key to the research’s success. “As we identified areas we were lacking, we looked at new cutting-edge technologies, and if there was something that didn’t meet our needs, we developed new assays to address our needs,” he says.

The lab of Karl Scheidt, Ph.D., professor of chemistry and professor of pharmacology; director of the Center for Molecular Innovation and Drug Discovery; and executive director of the NewCures accelerator at Northwestern University, was responsible for the design and creation of new molecules which were then evaluated by Bergan’s team for their ability to inhibit cell motility. Using chemical synthesis approaches, Scheidt and team accessed new compounds that minimized motility in tumor cells, with few side effects and very low toxicity.

“We’ve taken a clue provided by nature and through the power of chemistry created an entirely new way to potentially control the spread of cancer,” Scheidt says. “It’s been a truly rewarding experience working together as a team toward ultimately helping cancer patients.”

Refining the drug

Bergan notes the process for narrowing down the specific drug compound was a process of refinement. “We started off with a chemical that stopped cells from moving, then we increasingly refined that chemical until it did a perfect job of stopping the cells with no side effects,” he says. “All drugs have side effects, so you look for the drug that is the most specific as possible. This drug does that.”

Bergan says the key to this drug was engaging the heat shock proteins—the “cleaners” of a cell. “The way the drug works is that it binds to these cleaner proteins to stop cell movement, but it has no other effect on those proteins.” He says it is a very unusual, unique mechanism that “took us years to figure out.”

“Initially, nobody would fund us,” Bergan says. “We were looking into a completely different way of treating cancer.”

Next step: testing the drug in humans

Ultimately, Gordon says the goal of this research is to look for a new therapeutic to benefit humans.

“The eventual promise of this research is that we’re working toward developing a therapeutic that can help manage early stage disease, preventing patients from getting the more incurable later-stage disease,” he says. He’s quick to note this work has not been tested in humans, and doing so will require both time and money. The team’s best estimate is that will take about two years and five million dollars of funding. They are currently raising money to do IND (investigational new drug) enabling studies, a requirement to conduct a clinical trial of an unapproved drug or an approved product for a new indication or in a new patient population.

In addition, Drs. Bergan and Scheidt have founded a company, Third Coast Therapeutics, aimed to bring this type of therapy to patients.

“Our eventual goal is to be able to say to a woman with breast cancer: here, take this pill and your cancer won’t spread throughout your body. The same thing for patients with prostate, lung, and colon cancer,” Bergan says. “This drug is highly effective against four cancer types (breast, colon, lung, prostate) in the in vitro model so far. Our goal is to move this forward as a therapy to test in humans.”

Bergan says his team feels lucky to have the opportunity to conduct this challenging research at the OHSU Knight Cancer Institute, an institute dedicated to novel approaches to detecting and treating cancer.

“What early detection is trying to do is detect an early, lethal lesion. Cancers are lethal because they move,” he says. “This drug is designed to stop that movement.”

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A NEW STUDY FOCUSES ON A BREAKTHROUGH IMMUNO-ONCOLOGY DRUG COMBINATION

by Daniel Dupuis

A number of immuno-therapies formulations for the treatment of cancer have been developed in a quest to extend patient survival rates, while also mitigating life-altering side effects and safety concerns. While no current or proposed drug can make this claim, a recently published study that was featured in the British Journal of Cancer provides data that indicates that the initial promise of immunotherapies has been realized.

Previous studies have demonstrated that Aneustat™ is not only effective as a stand-alone oncology therapy, but can also best be described as a “foundational” drug for combination cancer therapy. Aneustat™ has been paired in studies with a wide array of oncology medications that have been recognized as standard-of-care therapies and the results have consistently demonstrated that the addition of Aneustat™ offers dramatically improved outcomes and reduced drug resistance, thereby, expanding the therapeutic window.

A recently published study, Treatment with docetaxel in combination with Aneustat leads to potent inhibition of metastasis in a patient-derived xenograft model of advanced prostate cancer, Qu, et al.,1 11/doi:10,1038/bjc.2017,474, appears in the British Journal of Oncology and assesses the therapeutic advantages of combining Aneustat™ with docetaxel for advanced stage prostate cancer.

The study utilizes the patient-derived cancer tissue xenograft mode, which is the preferred methodology of the National Cancer Institute.

Docetaxel + Aneustat™ markedly inhibited C4-2 cell migration and LTL-313H lung micro-metastasis/kidney invasion. The drug combination downregulated expression of cancer driver genes such as FOzM1 (and FOXM1-target genes).

Aneustat™ has been clinically proven to boost the immune system to kill cancer cells thru aptosis and regulate the metabolic system (tumor microenvironment) to stop proliferation while therapeutically affecting 1750 cancer related genes.

These results confirm earlier results by the same researcher that demonstrated that Aneustat™ alone was more effective than docetaxel for tumor shrinkage and inhibition of cancer cell growth. The combination of docetaxel and Aneustat™, however, was superior to either drug as a single agent.

The significance of this study is considerable in that it not only demonstrates improved efficacy, but offers a combination therapy that is also safer, while reducing the debilitating side effects common to oncology medications.

This study is a part of a series of studies that demonstrate that Anuestat™ has improved the overall efficacy of a wide array of medications known to be accepted as first-line therapies for prostate cancer, including enzalutamide, bicalutamide, abiraterone and apalutamide. Of even greater significance, however, is that Aneustat™ has been proven to be effective against tumors that have already been deemed to be resistant to these medications. This indicates that the various combination therapies will be viable for a longer period of time than any single agent.

  

More than 1 in 10 men will be diagnosed with prostate cancer at some point in their lives, and 1 in 41 will die of the disease, making it the second leading cause of cancer death in American men, according to the American Cancer Society. Additionally, a recent report states that while the incidence of most cancers is in decline, late stage prostate cancer has risen since 2015.

Aneustat™/docetaxel is entering phase III trials and it is anticipated that it will be a fast track candidate for approval in 2020. This conclusion is based on the fact that the major obstacles that confront phase III candidates have been addressed in previous studies. Aneustat™ is non-toxic, with a negligible side effect profile (minor nausea) and no apparent safety risks. As a multi-target immuno-therapy, it can prevent, rather than be a contributing factor to the onset of co morbidities.

This recent study confirms that Aneustat™ is a foundational drug that can be combined with numerous standard of care medications that can improve overall efficacy, while reducing side effects and safety concerns and mitigate the inherent drug resistance associated with current oncology medications.

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CAN A NEW DEVEOPMENT MODEL PREVENT COSTLY PHASE III DRUG DEVELOPMENT FAILURES?

by Daniel Dupuis

Attaining FDA approval for a new drug is certainly the ultimate goal of any drug research initiative. Accelerating that process can not only prove to be beneficial to patients, but is also a key component of increasing the return on investment for any entity that has a vested interest in a new medication.

Due to decreased productivity, the internal return on investment for research and development within the pharmaceutical industry has been sliding for years, and reports have indicated that it is already below break-even when the cost of capital is included and it will continue to fall in the ensuing years.

Pharmaceutical companies share the characteristics of many large, multi-national corporations that have enjoyed substantial profits for decades in that they suffer from corporate paralysis. The ramifications of this malady have resulted in them being slow to adopt new development models.

One methodology that can offer great benefits to pharm aceutical companies is the patient-derived xenograft (PDX) model. Oncology has been the recipient of the largest share of venture capital over the last few years, with immuno-therapy being an area of considerable focus and the PDX model is especially applicable to this sector.

In a PDX model, a live human tumor is grafted onto an immuno-deficient mouse and the results have demonstrated that it very closely replicates the therapeutic responses that take place in human trials. This allows companies to predict outcomes in the early stages of development and make the decision to abandon, or alter the molecular structure of a drug, long before the start pf pivotal Phase III trials.

What is the value of such a model? Companies often spend $700 to $800 million in development before they reach the pivotal Phase III trials. One only has to scan recent biotech news stories to quickly realize that adoption of PDX models, when applicable, will soon be viewed as the preferred methodology.

On April 6th of this year, shares of Incyte plummeted 23% in one day, while Merck shares fell 2.5%, on the news that the results of the Phase III trial of the combination of Merck’s Keytruda and Incyte’s epacadostat failed to show a significant improvement in efficacy over Keytruda as a stand-alone therapy. This unexpected outcome also cast doubt on other similar drugs in development and NewLInk Genetics saw its stock plummet by 42.6%.

A similar scenario befell Jounce Therapeutics on June 4th of 2018 as its stock fell 38% in one day when their drug candidate, JTX-2011, failed to deliver robust patient responses, either as a stand-alone treatment, or in combination with Opdivo (Bristol-Myers Squibb), against a range of solid tumor cancers.

The aim of immuno-therapy is to deliver efficacy, while either minimizing, or eliminating, the debilitating side effects of current cancer medications. In light of the precipitous drop in stock price of the aforementioned companies, recent criticism has now focused on the fact that none of the new formulations had any demonstrated efficacy as stand-alone therapies prior to being combined with current standard of care drugs.

There are current medications that are already in the marketplace, or in development, that have implemented the PDX model with unparalleled success. Of note, is that these single medications have been shown to be effective against several forms of cancer, which is a direct result of PDX models identifying biomarkers of therapeutic responses and allowing for numerous tests to be conducted at a cost effective rate.

Abraxane™, a cancer drug developed by Celgene, effectively utilized PDX models. It is a protein-bound paclitaxel in an injectable form that is used to treat breast cancer, lung cancer and pancreatic cancer. In June 2010, positive results were published for a Phase III trial for NSCLC (non-small cell lung cancer) when compared to solvent-based paclitaxel and Abraxene™ was approved in 2012 for the treatment of NSCLC. In September of 2013 it received approval for use in treating advanced pancreatic cancer as a less toxic alternative to FOLFIRINOX.

An immuno-oncology drug candidate that is now poised to enter a Phase II/III trial is perhaps the best example of how a PDX model was used to identify therapeutic responses for prostate cancer and also for its pipeline development. Aneustat™, a multivalent foundational drug developed by Omnitura Therapeutics, used a PDX model to derive their pre-clinical data proving Aneustat’s efficacy, both as a monotherapy and as a combination therapy with docetaxel, while exhibiting reduced toxicity, side effects, and drug resistance.   

The high rate of predictability of the PDX cancer model makes their upcoming pivotal trial much more of a foregone conclusion than a high level risk.

HOW A SHIFT IN DEVELOPMENT STRATEGY MAY AFFECT INVESTMENT

Venture capital over the last few years has focused almost exclusively on early-stage companies, while limiting investment in mid or late stage biotech companies. This is understandable in that the chances of successfully completing Phase III trials to the satisfaction of the FDA are 1 in 5. The emergence of the PDX model, however, may dramatically change this assessment as it directly mirrors what may transpire in Phase III trials, but in the early stages, when it’s cost effective. Would a a venture capitalist be far more willing to invest in a drug prior to a Phase III trial if their predictive model indicated their successful outcome was probable rather doubtful?

Some companies may be hesitant to utilize the PDX cancer model, as the results may not be favorable and companies have attracted substantial investment and/or shareholder capital long before proof of concept. Now that PDX models are known to accurately mirror therapeutic responses in human trials, however, investors may ultimately demand their inclusion.

Considering the enormous cost of the aforementioned Phase III failures, special attention should be focused on the utilization of PDX models and the drugs that are developed utilizing this strategy. It is ultimately cost effective and will be of great benefit to patients that are in need of safe and effective new therapies.

*The number of PDXs evaluated

The Predictive Value of PDXs for Clinical Outcome

A recent pooled study has been published that provides a clear relationship between PDXs and human clinical trials. In fact, it not only indicates how efficacious a medication may be, but also allows for targeting specific characteristics. For example, the study of non-small cell lung cancer indicated that Gefitinib was effective, but only with the EGFR Exon19 Del mutation, while EGFR wild-types were rendered ineffective. This directly correlates with the results accrued from the human studies. These results are indicative of the value of the PDX model, as it allows for the development of new drugs within a narrow parameter and provides valuable information in the early stages of development.

CONCLUSION:

It is clear that the utilization of PDX models in the development of cancer drugs is an increasingly valuable tool that is not only cost effective, but will help companies to more quickly develop medications that have considerably better odds of being ultimately approved.

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NEW DRUGS ON THE HORIZON 2018

by Daniel Dupuis

There are a number of new drugs in late stage trials that may soon become available to patients suffering from a wide array of either life threatening diseases or conditions that significantly affect a person’s quality of life.

There is, however, both good and bad news for people that are in need of these new medications. The pharmaceutical business is just that, a business, and they are going to dedicate their resources to drug candidates that offer the most revenue potential. This is good news if you suffer from a disease that is share d by a significant portion of the population, but perhaps not for those that are afflicted with a a rare illness.

Luckily, they still do conduct research for diseases that only affect a relatively small percentage of the population, but the price for these new medications can be staggering. For example, a company called Spark can now cure a rare form of blindness, but the price tag is $850,000, while a new drug for hemophilia has now earned the dubious distinction of now being the world’s most expensive medication at a cost of $1.5 million. While this certainly seems outrageous, insurance companies will embrace this new drug as it cures, rather than treats the illness, and they currently spend $800,000 a year, every year to manage this specific form of hemophilia.

Fortunately, there are a number of drugs in late-stage develop ment that may help the millions that suffer from the not-so-rare illnesses.

PAIN

In an admittedly crowded news environment, perhaps no other story has received more recent attention than the opioid crisis. The ravaging effects of opioid addiction have wreaked havoc on not only families, but entire communities. Due to increased scrutiny, physicians are rightfully afraid to even consider writing any pain medication. The other side of the story, however, is rarely told. A recent  HYPERLINK “https://nccih.nih.gov/news/press/08112015” \t “_blank” analysis from the National Institute of Health estimates that more than 25 million people in the United States (or over 11 percent of the country’s adult population) live with chronic pain. This means that they have experienced pain every day for the past 3 months. The majority of people taking medication for acute and/or chronic pain have a legitimate need for a solution.

The opioid problem is a relatively recent phenomenon and there has not been a new pain reliever to enter the market in over 50 years (ibuprofen), so most drug companies are only in the early stages of development and people suffering from pain are not really interested in something that may not be available for ten years or more.

Scientists at Eli Lilly partnered with Pfizer in 2013 to work on a new type of non-opioid pain medication called Tanezumab. It works by blocking what are called nerve growth factor inhibitors and has now been fast-tracked for approval by the FDA.

Early indications are that it provides substantial pain relief, but without any of the accompanying euphoria that can lead to addiction. This will be a welcome option that can help patients suffering with chronic, or even acute pain and allow physicians to again prescribe a medication without limitations.

MACULAR DEGENERATION

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among people over 50 years of age. The condition isn’t curable, but there are current injectable treatments available that can slow down the progression of the disease.

Holding back macular degeneration requires constant dosing, and patients are obviously not so thrilled about regular eyeball jabs. But Novartis has had encouraging results from their recently completed phase 3 testing of brolucizumab. It can e xtend the time between injections to 12 weeks from the current 8-week schedule required by Elyea.

While the idea of getting a needle inserted in the eye is certainly horrific, for those that suffer from the dry version of macular degeneration, it would, most likely, be a welcome option. There are a number of drugs under development, but the variety of underlying causes may dictate that it will be a combination of medications that ultimately offers some progress. The implantation of camera-like devices does offer some hope, but may be years away. Unfortunately, the promise of stem cell therapies has proven to be ineffective and the FDA has cracked down on clinics that have promoted a variety of stem cell therapies. The only currently available option is to start, and continue, to take one of the various AREDs 2 formulas that are available as it has proven to slow down the progression of the disease. It can be costly as it is best to take it as soon as macular degeneration is detected and it must be taken in perpetuity, but there are now less expensive options available, just but be sure to carefully examine the ingredients.

HEART DISEASE

There have been promising new studies that link inflammation and heart disease, so it is no surprise that a pharmaceutical agent that can reduce inflammation could have substantial cardiac benefits.

Canakinumab has been used for juvenile arthritis, but has shown to h elp lower the risk of heart attack, stroke and cardiovascular death in people who have already had a cardiac event. Of special interest is that 50% of people at risk of a heart attack do not have high cholesterol, but do exhibit inflammation. This will allow physicians to target specific patients that do not present the obvious risk factors.

Canakinumab has reached it primary endpoints in a phase 3 trial (CANTOS trial), which should lead to a new indication for the drug to be used to treat heart disease.

CANCER

There are over 2000 new immuno-therapy drugs in development for the treatment of cancer, with a few already in the market. They aim to help the patient’s immune system combat cancer so that the debilitating side effects and/or safety concerns of current therapies can be mitigated. So far the results have been somewhat disappointing, but one new drug in that has completed phase 2 trials and is preparing to enter phase 3 may deliver on the initial promise of immuno-therapy.

Aneustat™ regulates 1750 cancer related genes, while significantly boosting a patient’s immune system. While most almost all cancer therapies, either new, or in development, are single target, Aneustat™ is multi-target and multi-functional. It is the first non-toxic formulation that has been proven to inhibit and/or kill active cancer cells. In trials, it has been paired with numerous drugs that are already in use, but can limit the life threatening side effects of standard cancer therapy, thereby, offering a new breakthrough therapy.

Additionally, Aneustat™ is an oral medication that will be offered for far less than the last three approved oral cancer therapies that cost approximately $170,000 per patient.

The unprecedented combination of efficacy, lack of side effects and ease of use have led many health organizations and insurance companies to champion Aneustat™, which is generally unheard of before the start of phase 3 trials.

BALDNESS

Sure, it may seem to be of little importance considering the aforementioned disease states and it is certainly not life threatening, but it can have a substantial effect on the perceived quality of life for both men and women. A common trait that is shared among people that say it is meaningless is that they generally have a full head of hair.

The researchers at Columbia University Medical Center found 75 percent of patients with moderate to severe alopecia showed “significant” hair regrowth after taking the drug ruxolitinib. Additionally, most drugs in development for alopecia only target men, but ruxolitinib does not affect hormone levels so it may be a viable option for both men and women.

By the end of the treatment 92% of patients had hair regrowth

Ruxolitinib is currently being used to treat a specific form of leukemia, but like many drugs, studies have demonstrated unintended outcomes that can benefit a large number of people. Remember, Viagra was being studied for high blood pressure and at the end of the trial most of the men, with perhaps a nudge from their wives, asked if they could stay in the study past its completion date.