Tag: neuroblastoma

Categories : Cancer PaediatricsTags :

Neuroblastomas: ‘New’ Immune System Responds Better to Therapy

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Credit: National Cancer Institute

Cancer researchers have shown that immunotherapy after stem cell transplantation effectively combats neuroblastomas in children. Crucially, stem cells from a parent provide children with a new immune system that responds much better to immunotherapies. These results of an early clinical trial were published in the Journal of Clinical Oncology.

Tumours of the nervous system, neuroblastomas are associated with an unfavourable prognosis if the tumour is classified as a high-risk type. and particularly poor for patients in the relapsed stage. In this study by scientists at St. Anna Children’s Cancer Research Institute and the Eberhard Karls University of Tübingen, immunotherapy following stem cell transplantation is now associated with long-term survival in a substantial proportion of the patients. Compared to an earlier study the survival rate was increased.

“After the transplantation of stem cells from a parent, the patients are equipped with a new immune system. This enables a better immune response to the subsequent immunotherapy and clearly improves the outcome,” explains Prof Ruth Ladenstein, MD, co-first author.

Five-year survival exceeds 50%

“After a median follow-up of about eight years, we see that more than half of the study patients live five years or longer with their disease,” Prof Ladenstein reports (5-year overall survival: 53%). In comparison, the 5-year overall survival in an earlier study, in which stem cell transplantation was not followed by immunotherapy, was only 23%. Those patients who showed a complete or partial response to prior treatment had significantly better survival.

“In summary, immunotherapy with dinutuximab beta following transplantation of stem cells from matched family donors resulted in remarkable outcomes when patients had at least a partial response to prior treatment,” says Prof Ladenstein. “In our study, there were no unexpected side effects and the frequency of graft-versus-host-disease was low.”

Restoring natural killer cell potency

Dinutuximab beta is a monoclonal antibody that binds to a molecule, GD2, on the surface of tumour cells, marking them for destruction by natural killer cells. But prior chemotherapies may impair natural killer cells. “Therefore, a transplantation of intact natural killer cells from matched family donors seems reasonable before immunotherapy is administered. The transplanted, new natural killer cells are now able to target the tumour cells more efficiently – by means of an antibody-dependent reaction,” explains Prof Ladenstein.

According to the authors, further studies are needed to determine the individual components of the therapeutic approaches. Recently, conventional chemotherapy has also been combined with immunotherapy early in the treatment strategy, resulting in similarly improved response rates. The hope is that a renewed immune system through a healthy parent in combination with the described transplantation procedure could further increase survival rates: “Our approach could thus result in stronger and longer lasting tumour control. A randomised study would be necessary to scientifically substantiate the additional potential benefit of a new immune system in the context of relapse therapy,” Prof Ladenstein adds.

Source: St. Anna Children’s Cancer Research Institute

Categories : CancerTags :

Duo of Existing Drugs Punishes Ravenous Cancer Cells

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Preclinical research from VCU Massey Cancer Center published recently in the Proceedings of the National Academy of Sciences shows that the combination of two existing drugs can kill aggressive neuroblastoma cancer cells by exploiting their metabolic ‘hunger’.

A cancer of the nervous system, neuroblastomas are one of the deadliest childhood cancers, and if the MYCN gene is overexpressed, the prognosis is even worse. Although paediatric blood cancers are more treatable thanks to medical advancements, it has been much harder to treat neuroblastomas mostly due to the difficulty of targeting MYCN.

“MYCN is a transcription factor, and it’s very difficult to drug transcription factors,” said study senior author Anthony Faber, PhD, co-leader of the Developmental Therapeutics research programme and Natalie N and John R.Congdon, Sr. Endowed Chair of Cancer Research at VCU Massey Cancer Center and associate professor in the Philips Institute for Oral Health Research at the VCU School of Dentistry. “So, the next best thing is to target what MYCN does in the cell. One thing it does is to crank up metabolic activity – what it’s doing to keep the cell alive – and we can work that against itself.”

Since these ravenous cells burn cellular energy stores as quickly as they can be replenished Prof Faber’s team looked for a method to kick their metabolism over the edge without harming normal cells.

Screening 20 metabolic drug combinations in cancer cells originating from nearly 1000 different patients, the researchers found that neuroblastoma with high MYCN expression was particularly sensitive to a cocktail containing two drugs: phenformin and AZD3965..

Phenformin was developed in 1957 to treat diabetes. It blocks complex I on the surface of mitochondria, the organelle where energy production occurs.

Although phenformin was taken off the US market in the 1970s after a number of deaths, it’s still in use elsewhere in the world and is finding new application in the US as a cancer drug. Right now, phenformin is being tested in phase I clinical trial for melanoma.

Meanwhile, AZD3965 is a much newer type of drug under phase I clinical investigation. It works by blocking MCT1 rectors on the surface of cells, in this case as a cancer treatment. MCT1 receptors ferry lactate, another energy source, out of the cell. Blocking MCT1 causes lactate to accumulate, causing the cell to stop using it to make energy.

Simultaneously targeting energy production with the two different pathways used by the drugs should result in disruption of the cellular power supply, stressing and finally killing the cells.

This idea was put to the test by using mice seeded with MYCN-amplified neuroblastoma patient cells. Greater tumour reduction was seen from the cocktail than either drug given alone, with the cocktail being well tolerated.

“The data we got with AZD3965 in combination with phenformin might get people to reconsider phenformin,” said study lead author Krista Dalton, MEng, PhD Student, Virginia Commonwealth University Philips Institute for Oral Health Research. “In combination, where we can use lower doses, phenformin might have better tolerability than it previously did on its own.”

Source: News-Medical.Net

Journal information: Dalton, K. M., et al. (2021) Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN-amplified neuroblastoma. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2009620118.

Categories : CancerTags :

Natural ‘Brake’ Keeps Neuroblastomas Benign

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Researchers have found that a signal molecule produced by Schwann cells found in benign neuroblastomas acts as a natural ‘brake’ keeping them benign and preventing their uncontrolled growth. This also works on malignant neuroblastoma cultures. 

While energising a tumour with a growth factor to halt it does not sound logical, with neuroblastomas the Schwann cells trigger the maturation of nerve cells and bring the growth to a halt.

Schwann cells produce a signalling molecule called epidermal growth factor like 8 (EGFL8). The researchers showed that EGFL8 stimulates the differentiation, or maturation, of neuroblastoma cells. “Until recently, we only knew that this protein existed, but its function was not known. We now for the first time know where EGFL8 is produced and how it acts,” explained study author Sabine Taschner-Mandl, PhD, head of the Tumor Biology Group at St. Anna Children’s Cancer Research Institute. The study results also showed that high levels of EGFL8 were linked to improved survival rates in neuroblastoma patients.

“In cell cultures, we have demonstrated that Schwann cells as well as their secreted signaling molecules exert anti-tumour effects, even in aggressive neuroblastoma cells. Thus, we are able to exploit a process that occurs naturally in benign neuroblastomas to stop the malignant ones,” Sabine Taschner-Mandl and her colleague Tamara Weiss, PhD, from the Medical University of Vienna, explained. 

However, there is still much to be discovered about how the interplay of Schwann cells with the rest of the body; currently the researchers are examining how they interact with immune cells.

The study also uncovered a significant finding: that Schwann cells in benign neuroblastomas have a similar cellular status to those that support healing in injured peripheral nerves. Schwann cells in the tumour were found to express repair-associated genes and demonstrated repair functions. “It is amazing that we have discovered a signalling molecule that plays a role in both tumour development of benign neuroblastomas and regeneration of injured nerves. Since EGFL8 stimulates the formation of nerve cell extensions, it could be of great importance for the treatment of injured nerve fibers”, said Tamara Weiss.

Source: Medical Xpress

Journal information: Schwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor like protein 8, Nature Communications (2021). DOI: 10.1038/s41467-021-21859-0

Categories : CancerTags :

Iron is a ‘Double-edged Sword’ For Cancer Cells

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A grant by the American Cancer society will be used to investigate the treatment of certain neuroblastoma by forcing them to overloading on iron.

Neuroblastoma is a cancer that forms in nerve tissue, and most commonly in the glands around the kidneys. It is the most frequently occurring childhood cancer that occurs outside the cranium. MYCN is overexpressed in 20-25% of neuroblastoma, and these cancers contribute to a considerable portion of paediatric cancer-related deaths. Recent research has shown that the MYCN gene introduces a weakness to ferroptosis-inducing drugs because MYCN draws on a lot of iron to help the cancer grow.  

“Iron is a double-edged sword in a cancer cell. It can help the cancer grow and survive, but it also creates these toxic molecules within the cell called reactive oxygen species,” explained Anthony Faber, PhD.

Reactive oxygen species (ROS) are unstable molecules that react with other molecules, causing DNA damage and cell death. This recently discovered form of cell death, largely influenced by iron accumulation, is called ferroptosis. Little is known about ferroptosis, and even less about cancers which may be vulnerable to ferroptosis-inducing drugs. By boosting cellular toxin removal systems, MYCN produces so much iron that it also creates a vulnerability to drugs which prevent cells from eliminating ROS. Blocking these toxin removal systems causes death among MYCN-amplified cells. 

“As MYCN continues to be one of the most important targets in cancer therapeutics, this study highlights a new and clinically important strategy for treating MYCN-associated cancers,” Dr Faber said.

“Fortunately, the Cancer Mouse Models Core run by Jennifer Koblinski, PhD, and Bin Hu, PhD, at Massey is spectacular and will allow us to robustly test these FDA-approved drugs in both patient-derived models and orthotopic models, where the tumors grow atop the adrenal glands similar to the way they grow in patients,” Dr Faber said.

If these models show positive results for the testing of these drugs, they can move on to clinical trials. He added that this study may have far reaching implications, as in certain small cell lung cancers and triple negative breast cancer, whose growth is driven c-MYC, a similar protein .

Source: Medical Xpress

Journal information: Konstantinos V. Floros et al, MYCN-amplified neuroblastoma is addicted to iron and vulnerable to inhibition of the system Xc-/glutathione axis, Cancer Research (2021). DOI: 10.1158/0008-5472.CAN-20-1641