Abstract CT095: Update: a phase 1/2, open-label study to assess safety, tolerability, biodistribution, radiation dosimetry and PET imaging characteristics of [18F]FPyGal in comparison to in-vitro diagnostic for the assessment of senescence in oncological patients (NCT04536454)

Abstract

Abstract It is well established that senescence of cancer cells can be induced by treatment with classical cytotoxic therapies but also by molecularly targeted therapies or immunotherapies, a phenomenon referred to as therapy induced senescence (TIS). Occurrence of intratumoral senescence harbors broad therapeutic implications and may limit the prognosis of cancer patients, as senescent cells, via their senescence associated secretory phenotype (SASP), can suppress anti-tumor immune responses and may increase the metastatic potential of non-senescent cancer cells. Preclinical data suggest that an eradication of senescent cells (senolytic therapies) or an application of SASP modulating therapies might improve the outcome of systemic cancer therapies, however, as a prerequisite to guide such approaches, robust and non-invasive modalities to visualize and quantify intratumoral senescence are needed. We recently reported on the safety evaluation of the novel Positron-Emission-Tomography (PET) tracer [18F]FPyGal, a radiolabeled substrate of senescence-associated ꞵ-galactosidase in healthy volunteers (AACR 2022, #7958). In summary, our data showed that the use of [18F]FPyGal is safe and well-tolerated in the described human study population. In the second stage of our trial, we are now investigating the concordance of histopathological senescence markers with [18F]FPyGal senescence signals in i) rectum cancer-, ii) non-small cell lung cancer- and iii) adenocarcinoma of the esophagogastric junction (AEG) patients, who are undergoing neoadjuvant therapy. Here, we report on patients from the rectum cancer cohort of the trial. [18F]FPyGal PET imaging was done before and after administration of neoadjuvant radiochemotherapy (RCTx). [18F]FPyGal PET signal was correlated with immunohistochemical senescence markers (p16, p21, p53) and quantification of SA-ß-gal (Senescence-associated beta-galactosidase) positive cells in biopsy materials (pre-therapy) and surgical resection materials (post-therapy). Expectedly, senescent cells were only detected at very low frequency in therapy naïve tumors and the lack of histological detection of senescence correlated with negativity in [18F]FPyGal imaging. In stark contrast, homogenous senescence, quantified with the indicated senescence markers, was detected in the majority of cancer cells after RCTx. Interestingly, in one rectum carcinoma, which underwent a full remission after RCTx, senescence of stroma cells in the area of the former tumor bed was detected by PET imaging and histologically. Collectively, our data indicate the utility of [18F]FPyGal PET imaging to non-invasively detect senescence. Future trials using [18F]FPyGal to guide oncological therapy, e.g. to apply senolytic drugs in a personalized manner, are warranted. Citation Format: Christian LaFougere, Brigitte Gueckel, Helmut Dittmann, Nils Trautwein, Martina Hinterleitner, Jonathan Cotton, Gerald Reischl, Gabriele Kienzle, Stephan Singer, Cihan Gani, Ulrich Lauer, Bernd Pichler, Lars Zender. Update: a phase 1/2, open-label study to assess safety, tolerability, biodistribution, radiation dosimetry and PET imaging characteristics of [18F]FPyGal in comparison to in-vitro diagnostic for the assessment of senescence in oncological patients (NCT04536454) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT095.