Specific therapies for Adamantinomatous Craniopharyngioma (ACP)

Fast facts

• Official title: Identifying directed therapies for adamantinomatous craniopharyngioma (ACP) using advanced biological techniques and genetically engineered pre-clinical models
• Lead researcher: Dr Todd Hankinson 
• Where: University of Colorado, USA
• When: September 2018 – August 2023
• Cost: £1.058 million over five years
• Research type: Paediatric, Craniopharyngioma (Low Grade), Academic
• Grant round: Quest for Cures

---

What is it?

Adamantinomatous craniopharyngiomas (ACPs) are a devastating type of brain tumour usually occurring in children.
These tumours are heterogeneous, which means they are made up of different types of cells, but they can also be partly solid and partly cystic (fluid). Their position in the brain also makes it unclear whether these tumours are ‘protected’ by the blood brain barrier.

Previous research has shown that the different types of cells that make up ACPs communicate with each other using chemical messengers called cytokines. Cytokines are molecules released from cells that allow them to ‘talk’ to each other and promote survival and growth.

Cytokines are also important because the healthy immune system uses them to promote inflammation when needed. Researchers suspect that in ACP these chemical messengers are promoting tumour growth but we need to know more.

Dr Todd Hankinson, a neurosurgeon at the University of Colorado, will lead a five-year research grant using different techniques to achieve three broad aims:

Aim 1. Understanding how ACP cells communicate

Because ACPs are made up of different types of cells, Dr Hankinson’s team will separate out individual cells from the tumour. They will then look at their RNA codes to find out which ones are producing key cytokines.

They will also use emerging research tools to show where in the tumours different cytokines are present. These innovative tools, called Multiplexed Ion Beam Imaging (MIBI) and Cleared Tissue Digital Scanned Light-Sheet Microscopy (C-DSML), will be used alongside each other to find out where different cytokines are being used within the tumour mass.

If we know how and where the tumour cells are ‘talking’ we have a better chance of stopping them communicating, and so stopping them growing.

Aim 2. Identifying treatments for ACP

When the research team know which cytokines are involved and if their activity can be blocked using drugs, they will test the best potential drugs in pre-clinical models.
For this work the Colorado team will be working closely with Professor JP Martinez-Barbera at University College London (UCL) and using his expertise in this type of modelling.
Treatments will be given systemically (not directly into the tumour) and the amount of drugs that are getting to the tumour will be measured.
Once the researchers confirm that one or more drugs are reaching the tumour in effective levels they will ask the questions, ‘Are the drugs killing the tumour?’ and ‘Which ones are doing it best?’

Aim 3. Testing treatments in the clinic

Following on from the pre-clinical modelling, the two most promising therapies will be tested in children with newly diagnosed ACP. The drugs will be given before a biopsy or surgical removal of the tumour to find out if the drugs are able to cross the blood–brain barrier (this is a Phase 0 trial).
With this information, the team will be able to design and start a larger clinical trial for new treatments for children with ACP.

Doing research on uncommon tumours is very difficult to do and having multi-national and multi-institutional support is very hard to find. The support provided by The Charity is critical to accelerate progress.

Dr Todd Hankinson

Why is it important?

ACPs are associated with the worst quality of life due to the location of the tumour – near the pituitary gland, optic nerve and hypothalamus. 

Almost all children with ACP suffer from a life-altering side effect or injury from the tumour itself or its treatment. These include hormone imbalances, blindness and morbid obesity.

The current standard of treatment includes surgical removal of the tumour, followed by radiation therapy. There are currently no targeted therapies to treat ACP, highlighting the need to better understand the biology of these tumours and develop improved therapies.

This research programme is bringing together researchers from University of Colorado Denver and Institute of Child Health, University College London, with expertise in basic and clinical research.

The researchers are part of a consortium called Advancing Treatment for Paediatric Craniopharyngioma that is dedicated to identifying and developing targeted treatments that will improve the quality of life of children with ACP.

Who will it help?

This research will help develop targeted treatments that will improve the quality of life of children with ACP and their families.

Research into ACP biology has been overlooked and nearly no novel therapies have been introduced for over 50 years, resulting in patients having the lowest quality of life. This research has massive potential for patient benefit.

Dr Todd Hankinson

Milestones

Achieved

In the first year of this grant the team have made great progress:

Aim 1) Dr Hankinson and his team have refined the technique they will be using to separate out the individual cells. They’re now using ethically-donated human ACP samples to find which cell types are producing the different cytokines.

They’re also working with technology specialists to adapt the MIBI machine so that it will give a clear picture of the chemical communication within a tumour.

Work on the C-DSLM imaging is also progressing with the team modifying techniques to see 3D relationships more clearly.

Aim 2) The pre-clinical modelling is also going well. The first drug candidate has been tested and the results are being analysed.

Aim 3) This is the most exciting from our perspective because it’s been accelerated beyond what we thought the grant would produce.

While we were assessing this grant for funding, the Phase 0 trial was funded elsewhere. This means that the group have been able to step up their timetable and we’re now funding their Phase II trial instead. (Phase I trials aren’t needed in this case because the drugs have already been tested for safety.)

A panel of experts from the CONNECT consortium assessed the data our researchers provided and accepted their proposal for treating a small number of children with an immunosuppressive drug alongside a type of drug called a MEK inhibitor. 

This shows how the work is racing towards the clinic.

Our latest update:

The team have developed a machine learning approach to generate synthetic data that is closely related to the original single cell RNA sequencing data from craniopharyngiomas. They hope this can be used to increase statistical power and make substantial cost savings in the future.
They investigated a type of drug called a MEK inhibitor (MEKi) which didn’t work as well as hoped in the lab. But the team have developed a new senolytic (drug that can put tumour cells to sleep) and plan to investigate MEKi and senolytics as a combination therapy.
Three patients have been recruited to the feasibility study at Colorado. The protocol has been finalised and the drugs are being sourced for the CONNECT Phase II trial.

Upcoming

In the next year the team will continue to optimise their techniques, predict and test new treatments with the ultimate goal in sight… getting new treatments into the clinic.