Team identifies mechanisms behind resistance to FGFR inhibitor drug

“FGFR represents an important therapeutic target in many cancers,” says lead author Lipika Goyal, MD, of the MGH Cancer Center. “Our findings may inform future strategies for detecting resistance mechanisms and inducing more durable responses in FGFR2 fusion-positive intrahepatic cholangiocarcinoma and possibly other cancers in which the FGFR pathway is being explored as a therapeutic … Continue reading “Team identifies mechanisms behind resistance to FGFR inhibitor drug”

“FGFR represents an important therapeutic target in many cancers,” says lead author Lipika Goyal, MD, of the MGH Cancer Center. “Our findings may inform future strategies for detecting resistance mechanisms and inducing more durable responses in FGFR2 fusion-positive intrahepatic cholangiocarcinoma and possibly other cancers in which the FGFR pathway is being explored as a therapeutic target.”

Cancers driven by mutations that activate FGFR include certain tumors of the lung, breast, stomach and bladder. From 10 to 20 percent of cases of intrahepatic cholangiocarcinoma (ICC) — the second most common tumor originating in the liver — are thought to be driven by FGFR2 fusion mutations. An FGFR inhibitor called BGJ398 is currently in a phase 2 clinical trial for treatment of advanced ICC patients whose FGFR-driven cancers progressed after chemotherapy, and while preliminary data from the trial reported a significant response to treatment, as with most targeted therapies, resistance inevitably develops.

The MGH team analyzed samples from three patients with FGFR2 fusion-positive ICC enrolled in the BGJ398 trial for whom treatment led to a 30 to 50 percent tumor reduction, followed by disease progression after four to eight months. Analysis of cell-free DNA (cfDNA) from blood samples taken before BGJ398 treatment and after tumor progression revealed that one to five new FGFR2 kinase domain mutations had developed in each patient. A common mutation that emerged in all three patients was FGFR2 V564F, a gatekeeper mutation which interferes with the binding of BGJ398 to the FGFR. The other mutations altered the conformation of FGFR2, leading to continuous signaling through the pathway.

Rapid autopsy samples from one patient who died after having disease progression on BGJ398 treatment revealed that different metastases harbored distinct FGFR2 mutations, thus demonstrating that multiple different mechanisms can confer resistance in individual patients. Treating BGJ398-resistant cell lines with several other FGFR inhibitors showed that other structurally distinct drugs in the same class may be able to overcome FGFR2 resistance mutations.

“As seen with the development of resistance to other targeted treatment drugs, the mechanisms we identified are heterogeneous, and different therapeutic approaches may be necessary to overcome those resistance mechanisms,” says senior and co-corresponding author Andrew X. Zhu, MD, PhD, director of Liver Cancer Research at the MGH Cancer Center. “In addition to helping us understand why patients developed tumor progression within months of beginning a rationally chosen targeted therapy, our findings also suggest that tumor biopsies may underestimate resistance mechanisms. Repeat analysis of cfDNA may provide a more comprehensive picture of the mechanisms at play.”

Men with learning difficulties four times more likely to die of testicular cancer

The UK study, which is presented at the European Association of Urology conference in London, has found that testicular cancer sufferers who also have learning disabilities (LD) have a 1 in 10 chance of dying from the cancer, as opposed to a 1 in 36 chance in the general population. As this is the first major study to look at cancer survival rates in people with learning difficulties, the authors don’t yet know if this increased mortality rate applies to all cancers or just to testicular cancer.

Around one and a half million people in the UK are classified as having learning difficulties. Research has found that males with intellectual disabilities die on average 13 years earlier than the general population. In females the situation is even worse, women with intellectual difficulties die on average 20 years earlier. Most of these deaths are believed to be due to cardiovascular disease, but now a group of UK scientists and clinicians have looked at the testicular cancer incidence and how it relates to learning difficulties.

Using the NHS’s Hospital Episode Statistics database, the team, based at the University of Birmingham identified 158,138 male patients with learning difficulties. Over a 14 year period from 2001 to 2015, they found that 331 had testicular cancer, and 32 died of cancer. In the general population 25,675 had testicular cancer with 713 cancer specific deaths, meaning that the rate of cancer deaths was significantly higher in people with learning difficulties.

The work’s lead author Dr Mehran Afshar (St George’s Hospital, London) said “We found that people with learning disabilities are not only more likely to develop testicular cancer, but are also far more likely to die from it than the general population. Testicular cancer is relatively rare, but if similar imbalances apply to all cancers, which we suspect to be the case, this would make excess cancer deaths associated with learning difficulties a significant public health issue. However, we don’t yet have any statistics to confirm this. We are still processing the data on other cancers, such as prostate, breast and colorectal cancer.”

“We propose that there might be several reasons which cause this disparity in survival, perhaps including the possibility that men with learning difficulties are not so good at self-examination, going to the doctor, and then following through with any treatment. It could also be that because consent is more difficult to obtain from these patients it affects the treatment they receive.”

Although cure rates for testicular cancer are high, it is the 3rd leading cause of cancer death amongst men aged 18 to 50. Between 1979 and 2006 there was an 82% increase  in incidence in Europe (although rates have been stable since). Several high-profile cases have raised the public visibility of testicular cancer in the recent years, the cyclist Lance Armstrong being the best known. Overall, cancers are less common in patients with learning difficulties, although this is changing as LD patients are generally living longer.

Commenting, Professor Jens Sønksen (University of Copenhagen) of the EAU Scientific Congress Committee said; “Recently we have seen an increased focus on inequality in health care as it appears that people of different backgrounds receive health care of different quality.

This study is important because it identifies a vulnerable group of patients at increased risk of cancer mortality. As health care professionals we will need to develop methods to provide better health care focused specifically on people with intellectual disabilities.”

Color change test to help cancer research advance

Researchers know that patients with several types of cancer, including prostate cancer, have higher than normal levels of a protein called AMACR, and that the protein is linked to the aggressiveness of the cancer. Lowering levels of AMACR reduces the growth of cancer cells, and these cells revert to more ‘normal’ behaviour.

However exploitation of these discoveries has been slow because of the lack of a test to easily measure functional levels of AMACR.

Now scientists from the Department of Pharmacy Pharmacology have created a simple and cheap test that turns a clear liquid bright yellow in the presence of the functional protein, within minutes. The research is published in the leading journal Chemical Communications.

Lead author Dr Matthew Lloyd, from the University of Bath Department of Pharmacy Pharmacology, said: “The research suggests new ways of treating cancer can be developed based on reducing AMACR function, which is exciting, but progress has been extremely limited because of the technical difficulties in measuring function.

“One of the important things about our test is that we can now quickly analyse samples and start investigating the development of new treatments based on reducing AMACR function. It will also allow investigation of the underlying biology, which is currently poorly understood. There is also potential for developing the method into a new way of monitoring the cancer. This is an extremely significant step forwards in the field.”

Using the new test many samples can be analysed quickly and at the same time, and the functional level of AMACR can be measured much more accurately than by previous methods.

Dr Iain Frame, Director of Research at Prostate Cancer UK said: “The development of new treatments to halt the spread of prostate cancer is crucial if we are to stop thousands of men dying from the disease every year. It has been known for some time that a protein called AMACR is involved in prostate cancer development. This makes it an exciting drug target, but until now, it has been difficult to test the effectiveness of potential new drugs on blocking the protein.

“Dr Lloyd’s research provides a key part of the puzzle which means we can start the process of developing drugs to target AMACR and ultimately fight the disease in men. We are proud to have funded this research and look forward to seeing further developments.”