Thuy Tran

Triple negative breast cancer (TNBC) and metastatic urothelial cancer (mUC) have poor prognoses with low survival rates. Treatment options for these metastatic solid tumors have been expanded through the introduction of checkpoint inhibitors (such as atezolizumab and pembrolizumab), systemic chemotherapy, or antibody-drug conjugates (ADC) directed against cell surface proteins like TROP-2 (Trophoblast cell surface antigen 2).A promising approach is to develop radiotheranostics using radiolabelled novel antibodies that target TROP-2 expression, a protein highly expressed in both TNBC and mUC. The concept utilizes  a TROP-2 specific monoclonal antibody, radiolabelled with alpha- or beta particle radiation for therapy or radiolabelled with gamma och positron radiation for diagnostics. This approach delivers therapeutic quantities of radioactivity specifically to the tumor cells while sparing normal tissues. The same antibody, radiolabelled with diagnostic radionuclides, tumors are detected by imaging modalities that are currently used in clinical practice. We believe that targeting TROP-2 with radiotheranostics might provide an effective treatment option with a favourable toxicity-benefit balance, and might be a better option for patients who do not respond to ADC or other later line systemic therapies. The project is currently in preclinical development and has high translational feasibility into patients within 4-5 years.

Neuroblastoma is the most common and most devastating solid tumor in children. Despite intensive multimodal therapy, long-term survival in high-risk disease is only 50% and chances of survival after a relapse are dismal. Neuroblastoma is a radio-sensitive tumor, making targeted radiopharmaceutical therapy attractive, by delivering radiation to the cancer cells, wherever they reside in the body. We are leading a European multicenter trial where the efficacy of radiopharmaceutical therapy with 177-Lutetium, is being assessed in high-risk neuroblastoma in children (LuDO-N trial). One of the greatest challenges is that patients who experience a relapse are severely weakened by the cancer and by previous therapy, and optimally this type of treatment should be given at an earlier time point. For this purpose, we aim to develop radio-pharmaceutical therapy based on 225-actinium or 211-astathine, that emits a significantly higher radiation energy within a very congined space, to deplete single, or small clusters of metastatic cells and thus prevent metastatic relapses. The overriding aim is to generate data to support a future clinical trial that utilises targeted α-particle therapy early in the course of the disease. By controlling the systemic disease early, we believe that the cure rates in high-risk neuroblastoma could be significantly improved. We aim to translate our results into a clinical trial in humans, within a time period of 5-10 years.

In Sweden, approximately 10,043 breast cancer diagnoses were made in women in 2020 and 1,385 women died of breast cancer in the same year. There is a great need for new and improved treatment options for disseminated breast cancer, and especially for women with disseminated triple negative breast cancer (TNBC). TNBC is a fast-growing disease that has the shortest expected survival of all breast cancer subtypes. One way to improve survival is the use of target-seeking radioactive drugs, suitable for both nuclear medicine diagnostics and molecular radiation therapy, so-called theranostic preparations and today constitute new treatment regimens in precision medicine. The overall aim of our multidisciplinary and translational project is to develop a diagnostic and a therapeutic method based on targeting radioactive antibodies that specifically bind to the TROP2 cell surface receptor, which is abundant in triple negative breast cancer (TNBC). In collaboration with Scilifelab, we are developing new specific antibodies that can be labeled with a radioisotope of gamma or positron radiation for diagnostics with nuclear medicine imaging techniques. The same antibody can be labeled with a radioactive alpha or beta radiation to irradiate tumors and thus treat cancer. The project is currently in the preclinical phase, i.e. the development of these drugs takes place through tests in cancer cells in vitro and in animal models. We hope within a short time (3-5 years) to be able to go ahead and test the method in a so-called 'first-in-human' study in patients with disseminated TNBC. We hope that the method will be gentle with fewer side effects compared to existing treatments, and will provide a significantly prolonged survival to the best possible quality of life. If the method works, it can also be evaluated for other types of cancer (eg ovarian-prostate, lung cancer) as this particular receptor is also expressed to a high degree in these cancers.