TYK2 as tumor dependency and immune-modulator in ALCL

Anaplastic large cell lymphoma (ALCL) often occurs in children but also in adults. Typical for this type of lymph gland cancer is the unnatural connection of chromosome 2 and 5, which leads to the junction of the NPM and ALK genes. Since ALK is a signal molecule, the merging with NPM leads to a permanently activated signal, which leads to increased growth and eventually to the development of lymph gland cancer. The usual chemotherapy currently cures almost 80% of the patients, but in 20% the cancer returns. In addition, due to the young age, there is a risk of secondary malignancies which are cancers that are caused by the therapy and which can occur later in the life of the patient. These facts make the development of better therapeutics a medical and ethical imperative! In first experiments we identified the enzyme TYK2 as essential for the survival of ALCL tumor cells. If the enzyme is switched off in human ALCL cells, they die and if TYK2 is inactivated in a model system of the disease, the course of the disease is very mild. TYK2 is of great interest because it is a molecule that can be used as a target for therapies. One year ago, TYK2 inhibitors were first used in the clinic. As expected, they did not have strong side effects and were used to treat autoimmune diseases such as psoriasis. We think that repurposing these inhibitors for this type of lymph gland cancer would be very promising. In this project we want to investigate the signaling pathways activated by TYK2 and to study the altered immune response of the body against the tumor caused by TYK2 inhibition. The latter is important because our previous data show that TYK2 inhibitors induce a protein called PD-L1. A lot of PD-L1 on the surface of the tumor makes it invisible to the immune system, thus making therapy more difficult. One way to solve this problem would be to combine TYK2 inhibitors with a blocker of the PD1/PD-L1 interaction such as Nivolumab. The effectiveness of such a strategy is tested in our project and may pave the way for a therapy that has fewer side effects and is more effective than current, highly stressful chemotherapy regimens.

New Hope for Treating Aggressive Blood Cancer Anaplastic Large Cell Lymphoma (ALCL) is a rare but aggressive type of blood cancer that mainly affects children and young adults. While some patients respond well to treatment, about 30% develop resistance, making it crucial to find new and more effective therapies. Two recent research projects have explored promising new treatment strategies for ALCL, offering hope for better outcomes. Repurposing an Existing Drug for ALCL Treatment One study has investigated whether an already approved drug, Deucravacitinib, could be used to treat ALCL-especially for patients who lack a specific genetic alteration (ALK-negative ALCL). Researchers found that this drug effectively slows down the growth of ALK-negative ALCL cells by blocking TYK2, a key protein that helps cancer cells survive. In both lab experiments and animal models, Deucravacitinib significantly reduced tumor growth. It also lowered levels of PD-L1, a protein that cancer cells use to escape detection by the immune system. This suggests that the drug may not only shrink tumors but also make it easier for the immune system to recognize and attack cancer cells. Additionally, researchers found that combining Deucravacitinib with Rapamycin (another existing drug) made the treatment even more effective. This combination strategy could offer a powerful new approach for patients with ALK-negative ALCL, improving treatment outcomes while using drugs that are already clinically available. A New Drug Targeting Cancer Cell Growth A second study focused on developing a completely new drug called CM14, which targets cancer in a different way. CM14 is derived from a natural compound and works by interfering with TUBGCP2, a protein crucial for cell division. By disrupting this process, CM14 prevents cancer cells from multiplying, ultimately causing them to die. CM14 has shown remarkable promise not only in ALCL but also in other types of blood cancers like T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, it even triggered cell death in prostate cancer cells resistant to chemotherapy, suggesting it could be useful in solid tumors as well. By attacking cancer through a new mechanism, CM14 represents an exciting step forward in precision medicine. Its ability to target different cancer types makes it a promising candidate for further development. Looking Ahead These two studies highlight exciting new directions in ALCL treatment. Deucravacitinib offers a faster route to new therapies by repurposing an existing drug, while CM14 introduces a completely new way of targeting cancer cells. Both approaches provide fresh hope for patients with treatment-resistant ALCL, and their potential use in other cancers makes these discoveries even more significant. With continued research, these findings could lead to more effective, personalized treatments that improve survival and quality of life for people with aggressive blood cancers.