Experimental drug shows promise

Cancer cell during cell division. Credit: National Institutes of Health

A collaboration between Saïd M. Sebti, Ph.D., chair of Moffitt Cancer Center’s Drug Discovery Department, and Michele Pagano, M.D., chair of the Department of Biochemistry and Molecular Pharmacology at New York University’s Langone Medical Center, led to the publication of an important study in the latest issue of Nature. The investigation found that the drug, geranylgeranyltransferase inhibitor GGTI-2418 suppresses a new defective PTEN cancer pathway discovered by Pagano’s group.

Fully functional PTEN is well known to suppress tumor growth by antagonizing the PI3K/Akt tumor survival pathway. Pagano’s group discovered a novel mechanism by which PTEN protects cells from cancer by preventing the geranylgeranylated protein FBXL2 from binding and degrading IP3R3. IP3R3 is an important anti-cancer “sensor” recognizing hyper-proliferating cells that use abnormally high levels of energy, and targeting them to self-destruct as an anti-cancer safety mechanism. The PTEN gene binds to IP3R3, protecting its cancer-sensing function. However PTEN is defective in many cancers, and as such, FBXL2 is left unchecked; too much IP3R3 is degraded and fast-multiplying cells are less able to self-destruct.

“FXBL2 may be partially responsible for cancer growth in the many patients with genetic changes that happen to disable PTEN,” said Pagano. The drug GGTI-2418 blocks this cancer-causing activity of FBXL2 by inhibiting its geranylgeranylation which is required for FBXL2 to bind and degrade IP3R3. GGTI-2418 was co-discovered and developed by Sebti and NYU President Andrew Hamilton, Ph.D., while he was at Yale University. .

Another fascinating consequence of this discovery is that cancers with defective PTEN activate two tumor survival circuits to evade cell death, the PI3K/Akt and the FBXL2 pathways. “These findings have important translational implications as patients whose tumors harbor defective PTEN may benefit greatly from a combination of inhibitors of FBXL2 geranylgeranylation, such as GGTI-2418, and inhibitors of Akt, such as TCN-P,” said Sebti. Both GGTI-2418 and TCN-P were co-discovered by Sebti and are now developed by the clinical-stage oncology company Prescient Therapeutics Ltd.

The researchers also found that using GGTI-2418 to block FBXL2 from degrading IP3R3 made the tumors in mice more vulnerable to photodynamic therapy (PDT).”This experimental drug, by itself and with a form of light therapy, countered FBXL2 to let abnormal cells self-destruct,” said Pagano “We will be looking to collaborate with Dr. Sebti on clinical studies combining GGTI-2418 with PDT or TCN-P in patients with low PTEN.”

Explore further:
Scientists discover metabolic pathway that drives tumor growth in aggressive cancers

More information:
Shafi Kuchay et al. PTEN counteracts FBXL2 to promote IP3R3- and Ca2+-mediated apoptosis limiting tumour growth, Nature (2017). DOI: 10.1038/nature22965

__

This article and images was originally posted on [Medical Xpress] June 14, 2017 at 03:05PM

Provided by: H. Lee Moffitt Cancer Center & Research Institute

 

 

 

 

Gene-Editing Technology Has Successfully Targeted Cancer’s “Command Centre”

The CRISPR gene-editing tool has already shown a lot of potential for helping doctors treat the most stubborn diseases, and now scientists have used it to target the “command centre” of cancerous tumours, stopping their growth and boosting survival rates in mice.

In this new study, CRISPR was aimed directly at fusion genes – formed when two genes combine to form a hybrid, resulting in abnormal proteins which often cause cancer or help it to grow.

These fusion genes also have a unique DNA fingerprint, which researchers from the University of Pittsburgh were able to use to hunt down and modify them. Specially engineered viruses were then applied to replace the fusion genes with cancer-killing ones.

“This is the first time that gene-editing has been used to specifically target cancer fusion genes,” says lead researcher Jian-Hua Luo. ” It is really exciting because it lays the groundwork for what could become a totally new approach to treating cancer.”

CRISPR lets scientists effectively cut and paste the DNA in cells to fix problems or make improvements, and it has already been used to boost immune cells in the fight against certain types of cancers.

In this case, the researchers went for one of the causes of growth, demonstrating a new way to tackle the disease.

A type of fusion gene called MAN2A1-FER was targeted – previously identified by the same team as being present in certain types of aggressive cancer in the prostate, liver, lungs, and ovaries.

“Other types of cancer treatments target the foot soldiers of the army,” explains Luo. “Our approach is to target the command centre, so there is no chance for the enemy’s soldiers to regroup in the battlefield for a comeback.”

Once modified, the CRISPR-edited, cancer-killing genes were injected into mice carrying human prostate and liver cancer cells. The tumours reduced in size by up to 30 percent, no secondary growths were noted, and all the mice survived until the end of the eight-week test.

In contrast, in a control group of mice that didn’t receive the treatment, the cancer tumours increased nearly 40-fold in size, metastasis or cancer spread was common, and all the animals died before the study ended.

Even better, because fusion genes only occur in cancerous cells, healthy cells are left alone.

This could give the new technique a big advantage over chemotherapy, which has numerous unwanted side effects on healthy parts of the body.

Tackling the fusion genes didn’t kill off the cancer altogether, but there is hope a refined process could make that a possibility for the future.

More research is also needed to see if this can work as well in humans as it does in mice, but as these were human cancers xenografted to mice, the work so far is much more promising than a traditional mouse study.

“[T]he genome approach described here should in principle be applicable to most human cancers carrying fusion genes,” the researchers conclude. paper.

The study has been published in Nature Biotechnology.

__

This article and images was originally posted on [ScienceAlert] May 2, 2017 at 02:07PM

by DAVID NIELD

 

 

 

Early Clinical Trial Shows ‘Cancer Vaccines’ Can Protect Humans From Tumours

New hope.

Cancer comes in many different forms, and it is not unusual for diagnosed patients to endure multiple kinds of treatments before one that is effective against their particular form of cancer is found.

If it takes too long for doctors to find the right treatment, the consequences can be fatal.

The severity of cancer has fuelled physicians and scientists from all walks of life to explore any possible solution, including those that seem natural to those that may at times seem unconventional.

Well, researchers are now taking vaccines, which typically target viruses and bacteria, and reworking them to zero in on the patient’s specific cancer cells.

Physicians and scientists led by Catherine Wu at the Dana-Farber Cancer Institute in Boston just presented their results of their new cancer therapy to the American Association for Cancer Research (AACR) in Washington, DC.

Their personalised vaccines have prevented early relapse in 12 patients with skin cancer, while also boosting patient immunity when combined with a cancer drug.

While earlier cancer vaccines targeted a singular cancer protein found ubiquitously among patients, these personalised vaccines contain neoantigens, which are mutated proteins specific to an individual patient’s tumour.

These neoantigens are identified once a patient’s tumour is genomically sequenced, providing physicians with the information they need to pinpoint unique mutations.

Once a patient’s immune system is provided a dose of the tumour neoantigens, it can activate the patient’s T cells to attack cancer cells.

Unlike previous attempts towards cancer vaccines, which did not produce conclusive evidence in halting cancer growth, Wu’s team made their personal vaccine much more specific to each patient’s cancer, targeting about 20 neoantigens per patient.

The vaccines were injected under the patients’ skin for a period of five months and indicated no side effects and a strong T cell response.

All of Wu’s patients who were administered the personal vaccine are still cancer-free more than 2.5 years after the trial.

However, some patients with an advanced forms of cancer also needed an some extra punching power to fend off their diseases.

Two of Wu’s patients who did relapse were administered an immunotherapy drug, PD-1 checkpoint inhibitor, in addition to the personalised vaccine.

Working in conjunction with the enhanced T cell response from the vaccine, the drug makes it difficult for the tumour to evade the immune cells. The fusion of the two therapies eliminated the new tumours from both patients.

But we can’t get too excited yet. While these results are promising, the therapies are relatively new and require much more clinical testing.

Many physicians around the world are working together to test the potency of neoantigens in order to verify if the vaccine works better than current immunotherapy drugs over a sustainable period of time.

Personalised vaccines are costly and take months to create, a limiting factor in providing care to patients with progressing cancers.

Still, this study is an encouraging sign for many oncologists who are interested in using the immune system to fight cancer.

More than a million new patients are diagnosed with cancer each year in the U.S. alone, and even in situations where the cancer is treatable, the available chemotherapy agents themselves can be very toxic.

If proven safe and effective, this personalised cancer vaccine could give patients around the world hope for powerful treatment with fewer side effects.

__

Join our fans by liking us on Facebook, or follow us on Twitter, Google+, feedly, flipboardand Instagram.

Check out our Flipboard magazine ESIST  If you enjoy reading our posts. All of our handpicked articles will be delivered to the flipboard magazine every day.

This article and images was originally posted on ScienceAlert | Futurism

By NEIL C. BHAVSAR & CHRISTIANNA REEDY, FUTURISM