Nav: Home

Blocking Ran protein reverses resistance of lung and breast cancers

October 04, 2016

Researchers at the University of Bradford have discovered a way to prevent chemotherapy resistance in lung cancer by blocking a protein found in cancer cells.

Suppressing this protein, called Ran-GTP, also causes cancer cells already resistant to the first-line chemotherapy treatment, gefitinib, to become re-sensitised to the drug.

The research, led by Professor Mohamed El-Tanani, at Bradford's Institute of Cancer Therapeutics in collaboration with Queen's University Belfast, also found that Ran-GTP could be used to predict prognosis in breast cancer patients.

Key to the findings - published today (04 October) in Oncotarget - is the relationship between Ran-GTP and another protein called c-Met, which has previously been linked to several cancers. Overexpression of c-Met is known to cause chemotherapy resistance in breast and lung cancer and drugs which inhibit its activity are currently undergoing clinical trials for treatment of lung cancer. Professor El-Tanani believes the new research shows that targeting Ran-GTP could be a more effective approach.

"Much is known about the activity of c-Met and its impact on cancer, but our research is looking at things a step earlier, by focusing on the protein that regulates c-Met - Ran-GTP," he says. "c-Met needs Ran-GTP to function, and in particular needs very high levels when it becomes over-expressed or mutates - as is the case in cancers. By blocking Ran-GTP, we were able to both undo the resistance caused by c-Met and prevent that resistance occurring. This shows that Ran-GTP could be a good therapeutic target for cancer treatment, particularly in lung and breast cancer."

High levels of c-Met in breast cancer tumours are generally accepted to be associated with poor survival, but the team made a further unexpected discovery. When they analysed tissue samples from 247 breast cancer patients, they found that patients with poor prognosis had tumours with high levels of both Met and Ran-GTP, rather than Met alone.

"This finding emphasises how the role of Ran-GTP, rather than the expression of c-Met alone, seems to be key to the progression of cancer," says Professor El-Tanani. "Even when c-Met was high and Ran was low, a patient's prognosis was much better. This means we might be able to use Ran levels to stratify patients to determine the most appropriate treatment, intervening with more aggressive treatments only in patients with high levels of both proteins. "

Although this study silenced Ran-GTP in lung cancer cells through genetic manipulation in the laboratory, the research team is already well down the road to finding a drug compound that can perform the same function.

"We've already screened millions of potential compounds that have the potential to inhibit Ran to find the most potent one in vitro and in vivo model systems as a preclinical validation," says Professor El-Tanani. "We now have two very strong candidates ready to move forward into clinical trials."

One candidate is a 'repurposed' drug that has been already pre-clinically validated in breast and lung cancer and is ready for clinical trials. As an existing drug, it's already known to be safe for use in humans and could be taken straight to Phase 2 trials. The second candidate is a peptide which has already been tested in animal models.

The University of Bradford is actively seeking further funding and investor support, and once secured, clinical trials for the two drug candidates could start within a few months.

"It's been a long road to get to this stage, but we're very excited about the clinical potential for Ran-GTP inhibitors," he says. "It would be wonderful to see new treatments that block this protein enter trials, hopefully prove their effectiveness in treating cancer and eventually reach the clinic."

Catherine Pickworth, Cancer Research UK's science information officer, said: "When cancer becomes resistant to chemotherapy it's a lot harder to treat. Excitingly, this study has identified a potential target to stop or even reverse cancer resistance to a chemotherapy drug called gefitinib. Now more research and clinical trials are needed to find and test a drug that will help patients whose cancers have become resistant to chemotherapy."

University of Bradford

Related Breast Cancer Articles:

Does MRI plus mammography improve detection of new breast cancer after breast conservation therapy?
A new article published by JAMA Oncology compares outcomes for combined mammography and MRI or ultrasonography screenings for new breast cancers in women who have previously undergone breast conservation surgery and radiotherapy for breast cancer initially diagnosed at 50 or younger.
Blood test offers improved breast cancer detection tool to reduce use of breast biopsy
A Clinical Breast Cancer study demonstrates Videssa Breast can inform better next steps after abnormal mammogram results and potentially reduce biopsies up to 67 percent.
Surgery to remove unaffected breast in early breast cancer increases
The proportion of women in the United States undergoing surgery for early-stage breast cancer who have preventive mastectomy to remove the unaffected breast increased significantly in recent years, particularly among younger women, and varied substantially across states.
Breast cancer patients with dense breast tissue more likely to develop contralateral disease
Breast cancer patients with dense breast tissue have almost a two-fold increased risk of developing disease in the contralateral breast, according to new research from The University of Texas MD Anderson Cancer.
Some early breast cancer patients benefit more from breast conservation than from mastectomy
Breast conserving therapy (BCT) is better than mastectomy for patients with some types of early breast cancer, according to results from the largest study to date, presented at ECC2017.
One-third of breast cancer patients not getting appropriate breast imaging follow-up exam
An annual mammogram is recommended after treatment for breast cancer, but nearly one-third of women diagnosed with breast cancer aren't receiving this follow-up exam, according to new findings presented at the 2016 Annual Clinical Congress of the American College of Surgeons.
Low breast density worsens prognosis in breast cancer
Even though dense breast tissue is a risk factor for breast cancer, very low mammographic breast density is associated with a worse prognosis in breast cancer patients.
Is breast conserving therapy or mastectomy better for early breast cancer?
Young women with early breast cancer face a difficult choice about whether to opt for a mastectomy or breast conserving therapy (BCT).
Breast density and outcomes of supplemental breast cancer screening
In a study appearing in the April 26 issue of JAMA, Elizabeth A.
Full dose radiotherapy to whole breast may not be needed in early breast cancer
Five years after breast-conserving surgery, radiotherapy focused around the tumor bed is as good at preventing recurrence as irradiating the whole breast, with fewer side effects, researchers from the UK have found in the large IMPORT LOW trial.

Related Breast Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#529 Do You Really Want to Find Out Who's Your Daddy?
At least some of you by now have probably spit into a tube and mailed it off to find out who your closest relatives are, where you might be from, and what terrible diseases might await you. But what exactly did you find out? And what did you give away? In this live panel at Awesome Con we bring in science writer Tina Saey to talk about all her DNA testing, and bioethicist Debra Mathews, to determine whether Tina should have done it at all. Related links: What FamilyTreeDNA sharing genetic data with police means for you Crime solvers embraced...