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Comparative analysis of cancer cell responses to targeted radionuclide therapy (TRT) and external beam radiotherapy (EBRT).

ABSTRACT: The vast majority of our knowledge regarding cancer radiobiology and the activation of radioresistance mechanisms emerged from studies using external beam radiation therapy (EBRT). Yet, less is known about the cancer response to internal targeted radionuclide therapy (TRT). Our comparative phosphoproteomics analyzed cellular responses to TRT with lutetium-177-labeled minigastrin analogue [¹⁷⁷Lu]Lu-PP-F11N (β-emitter) and EBRT (ɣ-rays) in CCKBR-positive cancer cells. Activation of DNA damage response by p53 was induced by both types of radiotherapy, whereas TRT robustly increased activation of signaling pathways including epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs) or integrin receptor. Inhibition of EGFR or integrin signaling sensitized cancer cells to radiolabeled minigastrin. In vivo, EGFR inhibitor erlotinib increased therapeutic response to [¹⁷⁷Lu]Lu-PP-F11N and median survival of A431/CCKBR-tumor bearing nude mice. In summary, our study explores a complex scenario of cancer responses to different types of irradiation and pinpoints the radiosensitizing strategy, based on the targeting survival pathways, which are activated by TRT.

SUBMITTER: Grzmil M

PROVIDER: S-EPMC9429584 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Comparative analysis of cancer cell responses to targeted radionuclide therapy (TRT) and external beam radiotherapy (EBRT).

Grzmil Michal M Boersema Paul P Sharma Ashish A Blanc Alain A Imobersteg Stefan S Pruschy Martin M Picotti Paola P Schibli Roger R Behe Martin M

Journal of hematology & oncology 20220831 1

The vast majority of our knowledge regarding cancer radiobiology and the activation of radioresistance mechanisms emerged from studies using external beam radiation therapy (EBRT). Yet, less is known about the cancer response to internal targeted radionuclide therapy (TRT). Our comparative phosphoproteomics analyzed cellular responses to TRT with lutetium-177-labeled minigastrin analogue [<sup>177</sup>Lu]Lu-PP-F11N (β-emitter) and EBRT (ɣ-rays) in CCKBR-positive cancer cells. Activation of DNA ...[more]

PMID: 36045419

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Project description:Rationale: Clinical interest in combining targeted radionuclide therapies (TRT) with immunotherapies is growing. External beam radiation therapy (EBRT) activates a type 1 interferon (IFN1) response mediated via stimulator of interferon genes (STING), and this is critical to its therapeutic interaction with immune checkpoint blockade. However, little is known about the time course of IFN1 activation after EBRT or whether this may be induced by decay of a TRT source. Methods: We examined the IFN1 response and expression of immune susceptibility markers in B78 and B16 melanomas and MOC2 head and neck cancer murine models using qPCR and western blot. For TRT, we used 90Y chelated to NM600, an alkylphosphocholine analog that exhibits selective uptake and retention in tumor cells including B78 and MOC2. Results: We observed significant IFN1 activation in all cell lines, with peak activation in B78, B16, and MOC2 cell lines occurring 7, 7, and 1 days, respectively, following RT for all doses. This effect was STING-dependent. Select IFN response genes remained upregulated at 14 days following RT. IFN1 activation following STING agonist treatment in vitro was identical to RT suggesting time course differences between cell lines were mediated by STING pathway kinetics and not DNA damage susceptibility. In vivo delivery of EBRT and TRT to B78 and MOC2 tumors resulted in a comparable time course and magnitude of IFN1 activation. In the MOC2 model, the combination of 90Y-NM600 and dual checkpoint blockade therapy reduced tumor growth and prolonged survival compared to single agent therapy and cumulative dose equivalent combination EBRT and dual checkpoint blockade therapy. Conclusions: We report the time course of the STING-dependent IFN1 response following radiation in multiple murine tumor models. We show the potential of TRT to stimulate IFN1 activation that is comparable to that observed with EBRT and this may be critical to the therapeutic integration of TRT with immunotherapies.

Project description:ObjectiveTo gather a deep qualitative understanding of the perceived benefits and impacts of External-Beam RadioTherapy (EBRT) and TARGeted Intraoperative radioTherapy (TARGIT-IORT) using Intrabeam to assess how the treatments affected patient/care partner experiences during their cancer treatment and beyond.Design and participantsA patient-led working group was established to guide study design and to help validate findings. Patients with experience of receiving EBRT or TARGIT-IORT were purposively sampled by Hampshire Hospitals NHS Foundation Trust. These patients had been offered both regimens as per their clinical features and eligibility. Semistructured interviews were conducted with 29 patients and care partners with lived experience of either EBRT (n=12, 5-day FAST-Forward regimen and n=3, 3-week regimen) or TARGIT-IORT (n=14). Thematic analysis was then carried out by two coders generating 11 themes related to EBRT or TARGIT-IORT.SettingSemistructured interviews were conducted virtually via Zoom during February and March 2023.ResultsA number of procedural grievances were noted among EBRT patients. EBRT was perceived as being disruptive to normal routines (work, home and travel) and caused discomfort from side effects. TARGIT-IORT was perceived by patients and care partners as the safer option and efficient with minimal if any disruptions to quality of life. The need for timely accessible information to reduce anxieties was noted in both cohorts.ConclusionsThis qualitative study found that patients perceived EBRT as being greatly disruptive to their lives. In contrast, the one-off feature of TARGIT-IORT given while they are asleep during surgery gives them the feeling of stamping out the cancer without conscious awareness. These insights can help healthcare staff and policy-makers further justify the incorporation of the treatment favoured by these patient perceptions (TARGIT-IORT) more widely in routine practice. Further research is planned to explore TARGIT-IORT in more diverse populations and in the 35 countries where it is an established treatment option.

Project description:BackgroundThe spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases.MethodsThis phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least - 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life.DiscussionThis trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases.Trial registrationRegistered with ClinicalTrials.gov, number: NCT02773966 (Registration date: 05/16/2016).

Dataset Information

Comparative analysis of cancer cell responses to targeted radionuclide therapy (TRT) and external beam radiotherapy (EBRT).

Publications

Comparative analysis of cancer cell responses to targeted radionuclide therapy (TRT) and external beam radiotherapy (EBRT).

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