Project B10

Targeting radio- and chemo-resistance in metastatic phaeochromocytoma/ paraganglioma

Approximately 15% of patients with phaeochromocytoma/paraganglioma (PPGL) develop metastases, with no approved treatment options available. During the first funding period, B10 contributed significantly to improving diagnosis of patients with germline mutations predisposing to metastatic disease by applying metabologenomics in tumour samples. We made significant advances in our PPGL models, most importantly by generating a mouse model of metastatic spread. We established cyclooxygenase 2 (COX-2) as a target for adjuvant treatment, supporting our approach of testing and developing different COX-2-targeting compounds as radiosensitisers for peptide receptor endoradiotherapy (PRRT).
PRRT using [177Lu]Lu-DOTA-TATE is associated with increased overall survival as first line therapy; however, it has been reported that some patients develop extensive metastatic disease after initial response to [177Lu]Lu-DOTA-TATE treatment. Very little is known about the mechanisms of tumour control in PPGL; hence, insights into the mechanisms of radioresistance and recurrence as well as immunomodulatory effects of PRRT are essential in improving treatment efficacy through careful patient selection and adjuvant therapy.
We aim to address these areas by elevating targeting efficiency through somatostatin receptor type 2 (SSTR2) upregulation, by investigating the influence of the genetic tumour background and the microenvironment on radioresistance, by characterising radiation induced tumour metastasis and progression in mouse models, and by optimising radiosensitisation compounds. Outcomes will be complemented by results from projects B11 and B12 investigating different pathways contributing to disease aggressiveness in PPGLs. Successful completion will have immediate effects on therapy decisions for patients with metastatic PPGL.

Aims

(I) Investigate neoadjuvant SSTR2-inducing treatments counteracting HIF2α-associated downregulation of SSTR2 to enhance [177Lu]Lu-DOTA-TATE therapy.
(II) Establish and characterise irradiated co-culture models of MPC cells with tumour-associated macrophages with a focus on HIF2α activation, SDHB impairment, and COX-2 disruption.
(III) Explore molecular characteristics of radiation-associated metastasis in disseminated MPC metastases models with HIF2α activation, SDHB impairment, and COX-2 disruption.

© SFB/TRR 205