Identifying new therapies for blood cancers in patients with A-T

University of Birmingham Research Team

Research Project information

Principal researcher: Professor Malcolm Taylor
Institute:  University of Birmingham
Cost: £128,810.50 over 24 months in partnership with BrAshA-T
Start Date: February 2018

What are the researchers proposing to do?
Patients with Ataxia Telangiectasia (A-T) have an increased risk of developing blood cancers. These patients do not have a protein called ATM which is important for response to chemotherapy treatment. Consequently, when receiving chemotherapy for their blood cancers A-T patients experience substantial toxic effects. Therefore, new less toxic, blood cancer-specific therapies are highly needed.

Malcolm and his team have developed an animal model in which new treatments can be tested. In this model all the mice lack the Atm protein and have reduced development of T cells, a combination which allows them to develop a variety of blood cancers that occur in human A-T patients. Upon investigation of these blood cancers the team noted that a protein called c-Myc is particularly active in cancer cells. In this study they will explore different ways of supressing the action of c-Myc.  They will use animals with developed blood cancers to test whether the addition of small molecules that inhibit c-Myc can stop cancer progression, and if these molecules can be used in combination with low doses of chemotherapy.  They are hoping that this study will provide new, non-toxic, and effective strategies for the treatment of blood cancers in A-T patients.

One third of A-T patients develop a malignancy, most frequently a blood cancer. Current management of these blood cancers imposes a great challenge as A-T patients exhibit an increased sensitivity to radio- and chemo-therapy. There are no A-T specific protocols for blood cancer treatments and A-T patients have to rely on therapeutic protocols that are designed for patients without A-T who are not radio-chemo sensitive.  In some A-T patients such treatments result in fatal toxicities. Consequently, therapeutic doses must be reduced meaning that they might be less efficient, thus increasing risk of disease relapse and further increasing suffering to the patient. Therefore, there is a real need to devise novel blood cancer treatments that will be specifically suited for A-T patients.

How will the research be done?
In the first instance the team will use blood cancer cells obtained from animals lacking the ATM gene and test the ability of novel, non-toxic compounds to kill these tumour cells in laboratory conditions.
Subsequently, they will focus on compounds with the most potent anti-tumour activity in laboratory conditions and test them in animals with blood cancer lacking the ATM gene.
Finally, they will explore combinations between novel agents and low dose chemotherapy and identify those that are effective against blood cancer in animals lacking ATM.

How could it make a difference to the lives of those affected by A-T?
The team will test small molecule inhibitors that are already in clinical trials. Given that these new compounds are already being assessed in other patients, they anticipate that following completion of this study in two years, they will be in a position to directly inform optimal treatment of the most frequent blood cancers in A-T patients.

If any of these new inhibitors prove to be efficient, the reduced toxicity associated with their use will be hugely beneficial for A-T patients. It will lessen problems associated with toxicities such as infection and bone marrow depletion.

These compounds have the potential either to completely replace chemotherapy or facilitate its use at significantly reduced doses, whilst retaining the same anti-tumour effect. Furthermore, as many of new compounds can be taken orally they have the potential to reduce the hospitalisation period and therefore improve the overall quality of life of A-T patients.