A 3-way deep investigation of DLK1 as a key modulator and target of ACC
Leonardo Guasti · Barbara Altieri · Michaela Luconi · James Pittaway (Queen Mary University of London · University of Würzburg · University of Florence)
Adrenocortical carcinoma (ACC) is a rare and aggressive cancer that develops in the adrenal glands, which are essential for steroid hormone production. ACC is difficult to diagnose and treat, and limited effective therapies contribute to poor patient outcomes. Due to its rarity, ACC remains under-researched and urgently requires the development of new, targeted treatments.
We have a long-lasting interest in studying cancer-associated antigens, which are proteins found on the surface of cancer cells, distinguishing them from normal cells. While some are present in healthy tissue, they are often more abundant or altered in cancer cells, making them ideal therapeutic targets. Our recent research has identified the antigen DLK1 as being one of such antigens. We have demonstrated that, in the normal adrenal gland, DLK1 is found in stem cells, which are cells capable of developing into hormone-producing cells (i.e. cells secreting cortisol, aldosterone or androgens). These stem cells, which we have localised in the outer part of the gland (called capsule) are very active during embryonic development but become mostly inactive after birth. Interestingly, DLK1 is switched back on at very high levels in ACC. We don’t yet fully understand what DLK1 does in a healthy adrenal gland or how it helps ACC to develop. By studying its role more closely and exploring whether it can be safely targeted with new treatments, we hope to open up a completely new approach to treating this rare and aggressive cancer.
A promising way to target DLK1 is with monoclonal antibodies (mAbs), which are engineered proteins that bind specifically to cancer cell antigens—much like a key fitting into a lock. Once bound, mAbs can eliminate cancer cells by activating the immune system, blocking signals essential for tumour growth, or delivering toxic agents directly to the cancer cells, thereby sparing healthy tissue.
This project aims to evaluate a novel mAb that targets DLK1 and determine its effectiveness in killing ACC cells. In addition, we will investigate the role of DLK1 in influencing tumour interactions with surrounding adipose tissue and how it affects how the disease develops, as well as testing the mAb with a combination of novel and existing cancer drugs. These studies will help determine the therapeutic potential of DLK1-targeting mAbs, determine the role of DLK1 in ACC and support the development of future clinical trials.
Importantly, this research is part of an international collaboration involving three PhD students. Students will benefit from secondments in the partner laboratories of all principal investigators, promoting cross-disciplinary learning and fostering strong scientific exchange. Further to this, biannual meetings with established patient support charities and proactive sharing of results will help to finesse each individual project to achieve the best overall outcome for patients with ACC.