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Preclinical models of epigenetic modulation to enhance responses to chemoradiation in locally advanced Pancreatic Cancer

Code: BC-DTP_2026_46

Title: Preclinical models of epigenetic modulation to enhance responses to chemoradiation in locally advanced Pancreatic Cancer

Primary Supervisor: Oliver Pearce

Email: o.pearce@qmul.ac.uk

Institute: Barts Cancer Institute

Secondary Supervisor: David Propper

Email: d.j.propper@qmul.ac.uk

Institute: Barts Cancer Institute

Lay Summary:

About one-third of patients with pancreatic cancer have tumours that are too advanced for surgery but have not yet spread to other parts of the body. Some of these patients can undergo treatment to shrink the tumour and make surgery possible. This treatment usually involves chemotherapy or a combination of chemotherapy and radiotherapy (chemoradiotherapy). However, the success rate is quite low—only about 20% of patients get enough tumour shrinkage to become eligible for surgery. For those who do not, life expectancy is often only about a year.

On the other hand, patients who do become eligible for surgery have a survival rate like those whose cancer was operable from the start. This makes pre-surgery treatment incredibly valuable. So far, no new drugs have been able to significantly improve tumour shrinkage when combined with chemotherapy or radiotherapy in pancreatic cancer. However, laboratory studies suggest that drugs targeting epigenetics, which control how genes are switched on and off, could work well when combined with chemotherapy or radiotherapy. These combinations have already shown success in other types of cancer.

We have shown that drugs that target epigenetic processes improve responses in laboratory models, and we now wish to combine these drugs with radiotherapy. The drugs we are testing are approved for human use and therefore, if successful, these combinations could be fast-tracked into clinical trials, offering new hope for patients with pancreatic cancer.

Aim:

Identify epigenetic modulators that enhance PDAC sensitivity to radiotherapy (± chemotherapy and immunotherapy), using clinically relevant preclinical models.

Objectives:

  1. Assess how epigenetic drugs alter cancer cell, CAF, and immune cell responses to RT in 3D co-culture models.
  2. Determine effects on CAR T‑cell trafficking and activation in an ECM‑based model.
  3. Evaluate therapeutic efficacy and immunological/stromal consequences of epigenetic–RT combinations in an immune‑competent orthotopic mouse model.
  4. Validate top combinations in human PDAC tissue slices that mirror patient therapeutic responses (34).
  5. Define transcriptional and epigenetic mechanisms underpinning synergy.

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