Breakthrough discovery could lead to’Kinder’ treatment for childhood bone cancer

July 13, 2020

Researchers at the University of East Anglia and the University of Manchester have made significant progress that can lead to the “Kinder” treatment of children with bone cancer and save lives.

Current treatments are obsolete, chemotherapy cocktails are outdated, and amputations are performed. However, despite all this, the 5-year survival rate is as low as 42%, mainly because bone cancer spreads rapidly to the lungs.

A new study, published today, identifies a set of key genes that promote the spread of bone cancer to patients’ lungs. Further experiments in mice with engineered human bone cancer cells lacking these important genes show that the cancer cannot spread to the lung.

The study was led by Dr. Darrell Green of Norwich Medical College, UEA and Dr. Katie Finegan of the University of Manchester.

Darrell was inspired to study childhood bone cancer after his best friend died of a disease in his teens. Today, for over 40 years, the team has made what could be the most important discoveries in the field.

Primary bone cancer is a type of cancer that begins in the bone. It is the third most common solid childhood cancer after the brain and kidneys, with approximately 52,000 new cases occurring worldwide each year.

It can spread rapidly to other parts of the body, and this is the most problematic aspect of this type of cancer. Once the cancer has spread, it becomes very difficult to treat.

About a quarter of patients have cancer that has spread by the time they are diagnosed. Approximately half of patients with recurrent apparent localized disease will later detect the spread of the cancer. These numbers have remained stagnant for over 40 years, with no major advances in treatment.

In high school, my best friend Ben Morley fell ill with primary bone cancer. During my study, I realized that this cancer was left behind in other cancers in terms of research and treatment advances, so his illness prompted me to do something. So I studied college and got a PhD. Ultimately working with primary bone cancer.

I want to understand the underlying biology of cancer spread, so I’ll intervene at the clinical level and develop new treatments so that patients don’t have to experience what my friend Ben has experienced. I can. Ultimately, we want to save lives and reduce the amount of surgery damage. “

Dr. Darrell Green, Norwich Medical College, UEA

The research team investigated the most common type of primary bone cancer called osteosarcoma.

The genetic factors that cause osteosarcoma are well known (TP53 And RB1 Structural deformation) However, little is known about what causes it to spread to other parts of the body.

Dr. Green says: “Because primary bone cancer spreads to other parts of the body very quickly, it’s very important to work out exactly why this happens.

“We have developed a new technique for the isolation of circulating tumor cells in the blood of patients. These cells are important for scientific research because they effectively carry out the metastatic process. This was very difficult because there was only one for every normal blood cell in the mouse, which took over a year to develop and cracked.

“It was also difficult because most studies investigating circulating tumor cells were done in common adult cancers, which differed greatly in how the cancer biology was so different.

“Because osteosarcoma is a less common cancer of sarcoma, you have to start from scratch not only to find these cells from the beginning, but to keep them alive and profile gene expression. did.”

After profiling tumors, circulating tumor cells (CTCs), and metastatic tumors from patient donors, they were able to identify a potential driver of metastasis known as MMP9.

This driver, which we identified, is well known for cancer, but is “unbearable” because it quickly becomes resistant to treatment or finds ways to prevent it from being targeted. Is also considered.

So I thought I’d try a little cleverer way to find the MMP9’s “master regulator” and be able to perform actions that “can’t take action”. “

Dr. Darrell Green, Norwich Medical College, UEA

The team has begun collaborating with researchers at the University of Manchester working on MAPK7, a proposed master regulator for MMP9, using a mouse model that includes osteosarcoma.

Together, they engineered human osteosarcoma cells and included a silenced version of MAPK7. They found that when these cells were placed in mice, the primary tumor grew much slower. Importantly, it did not spread to the lungs-even if the tumor had been left for a long time.

“Deepening further, our research shows that silencing of MAPK7 arrested metastasis, because its gene pathway hijacked certain parts of the immune system that caused spread. “Dr. Green said.

“This is really important because not only has a gene pathway associated with metastasis been created, but deletion of this gene pathway can actually prevent the spread of cancer in living animals. Through system hijacking, we also know how and why this is happening.

“The next step, already ready for execution, is to silence this pathway in the form of a treatment, now that we have shown how important this pathway is.

“If these findings are valid in clinical trials, the treatment must be far more kind compared to the harsh chemotherapy and life-altering limb amputation patients receive today, saving lives and improving quality of life. There is no doubt that it will improve.”

Dr. Catherine Feyngan, lead author at the University of Manchester, said: “It’s great to work with a team at Darrell and UEA. This stands for us to tackle the serious unmet need to find effective treatments after osteosarcoma has spread. This is the first result from the new co-operative, which is called OMeNet, which brings together researchers from all over the UK to study the spread of osteosarcoma in groups and to accelerate the discovery of new treatments.

“Using Darrel’s genetic insights from patient material, we were able to validate their study in a model of primary bone cancer. As a result, we are an important protein that promotes metastasis.” Highlighting a new potential treatment for metastatic bone cancer by targeting MAPK7, this study has revealed a new treatment option for osteosarcoma, which has changed over the past 40 years. This is something we have never experienced.

“The Finegan Lab is developing new drugs for MAPK7, which we hope to do in the future to benefit patients with primary bone cancer.

“I also thank the Friends of Rosie charity for funding the research in Manchester’s lab and for helping to study childhood cancer here in the northwest.”

Super strong sophie

One of the patients who donated the organization to the study was Norwich’s five-year-old “Super Strong” Sophie Taylor. She was first diagnosed with osteosarcoma in January 2018 and underwent surgery and chemotherapy to cut off part of her leg.

Sadly, Sophie was taken to hospital with dyspnea early in January 2019, one year after diagnosis. There her family was told to have extensive cancer in her lungs. She died on January 18, 2019.

Sophie’s father, Alex Taylor, said: “Sophie was diagnosed with osteosarcoma in January 2018. Unfortunately, it was in her lungs when it was discovered.

“When we were informed that chemotherapy necrosis was low, we were fortunate to set out to find additional options and get in touch with Dr. Darrell Green.

“We weren’t hesitant to donate Sophie’s tumor to the study, she also analyzed her DNA and RNA and linked it to other drugs to track it. That’s what we hoped for. It was great to give Darrel and fight in our corner.

“Unfortunately, Sophie’s journey didn’t go well, so we couldn’t try the options we had on the table, but I’m very pleased that Sophie helped me in that way.”

“We will continue to support Darrell and the work he does. Sophie’s future charity aims to support the continuation of bone cancer research so that future Sophie can achieve better results.

“I’m pleased to acknowledge Darrell’s work. He is a remarkable person and I am really grateful for his support during, after treatment and since Sophie’s death. Deserves the credit and recognition that he receives.

“Sophie is an out-of-world kid, showing unbelievable power and courage, and deserved much better results. She amputated her leg, gave her several months of hard chemotherapy, and had surgery. He just had to treat a terrible wound with and continue to do so, going to Snowdon’s top, playing football, becoming James Madison in Leicester City, and she affected many people around the world. We are very proud of how she fought, and she contributes to the life-saving studies of future children.

“We add this to her heritage, share it with Pride, and continue “Takea Sophie” as Sophie did, sticking our tongue out to cancer. Thanks to Darrell and I would like to share with you that your enormous effort has paid off. We are very proud of you. “

The study was led by UEA in collaboration with the University of Manchester, Earlham Institute, Royal Orthopedic Hospital in Birmingham, Royal Papworth Hospital in Cambridge, Epistem Limited, University of Sydney, Norfolk University, and Norwich University Hospital.