Know thy tumour: Biomarkers to improve treatment of molecular radionuclide therapy

O’Neill, Edward; Cornelissen, Bart

doi:10.1016/j.nucmedbio.2022.02.004

Cited by 3 publications

(7 citation statements)

References 132 publications

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“…In conventional EBRT, a clear dose-response relationship has been demonstrated for both tumour response and toxicity response (22). For RLT, a similar radiation dose-response relationship is expected, where the focus is not on administered activity (Bq) but rather on absorbed dose, i.e., radiation energy deposited per unit mass of tissue (Gy) (2,23).…”

Section: Current Clinical Practice Of Rlt Dosimetry and Its Shortcomingsmentioning

confidence: 90%

“…Biodosimetry could enhance this strategy by also considering the intrinsic radiosensitivity of the patient. As stated by O'Neil and Cornelissen (22), radiobiology-based biomarkers could be used, alongside dosimetry, to further understand normal tissue toxicity to refine as high as safely administrable (AHASA) thresholds for each RLT agent, as well as to determine the as low as reasonably achievable (ALARA) minimum dose thresholds which is necessary to obtain a satisfying therapeutic outcome. A dose-response relationship could be established between the radiation dose and radiobiological response for each tissue/individual patient (22).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Biodosimetry, can it find its way to the nuclear medicine clinic?

Bolcaen,

Combrink,

Spoormans

et al. 2023

Front. Nucl. Med.

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Personalised dosimetry based on molecular imaging is a field that grew exponentially in the last decade due to the increasing success of Radioligand Therapy (RLT). Despite advances in image-based 3D dose estimations, the administered dose of a therapeutic radiopharmaceutical for RLT is often non-personalized, with standardised dose regimes administered every 4–6 weeks. Biodosimetry markers, such as chromosomal aberrations, could be used alongside image-based dosimetry as a tool for individualised dose estimations to further understand normal tissue toxicity and refine the administered dose. In this review we give an overview of biodosimetry markers that are used for blood dose estimations, followed by an overview of their current results when applied in RLT patients. Finally, an in-depth discussion will give a perspective on the potential for the use of biodosimetry in the nuclear medicine clinic.

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Section: Current Clinical Practice Of Rlt Dosimetry and Its Shortcomingsmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Biodosimetry, can it find its way to the nuclear medicine clinic?

Bolcaen,

Combrink,

Spoormans

et al. 2023

Front. Nucl. Med.

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“…For example, de-Colle et al measured the speed with which yH2AX foci were resolved, and observed a high level of intrinsic radiation sensitivity in prostate cancer samples, after ex vivo irradiation with EBRT [20]. The relative ability of tumors to repair DNA damage, and deal with unresolved DNA damage, would provide an essential insight into the functional radioresistance of tumors to lutetium-177 based therapies, particularly with heterogenous neuroendocrine and prostate tumors [8]. A functional approach to assessing radioresistance towards EBRT has recently been demonstrated by employing an ex vivo RAD51 foci formation assay [21].…”

Section: Imaging Conceptmentioning

confidence: 99%

“…To establish a dose threshold that is as low as reasonably achievable to reliably treat each patient, a relationship between administered and radiation absorbed dose and tumor response is required. It is likely that a general cohort-based dose-response may not be possible for neuroendocrine tumors due to its inherent biological heterogeneity [8]. A dose-response relationship based upon SPECT-image dosimetry was found in a cohort of pancreatic neuroendocrine patients [9].…”

Section: Introductionmentioning

confidence: 98%

Imaging DNA damage response by γH2AX in vivo predicts treatment response to Lutetium-177 radioligand therapy and suggests senescence as a therapeutically desirable outcome

O’Neill¹,

Mosley²,

Cornelissen³

2023

Theranostics

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Rationale: An effective absorbed dose response relationship is yet to be established for Lutetium-177 based radionuclide therapies such as 177 Lu-DOTATATE and 177 Lu-PSMA. The inherent biological heterogeneity of neuroendocrine and prostate cancers may make the prospect of establishing cohort-based dose-response relationships unobtainable. Instead, an individual-based approach, monitoring the dose-response within each tumor could provide the necessary metric to monitor treatment efficacy. Methods: We developed a dual isotope SPECT imaging strategy to monitor the change over time in the relationship between 177 Lu-DOTATATE and 111 In-anti-γH2AX-TAT, a modified radiolabelled antibody that allows imaging of DNA double strand breaks, in mice bearing rat pancreatic cancer xenografts. The dynamics of γH2AX foci, apoptosis and senescence following exposure to 177 Lu-DOTATATE was further investigated in vitro and in ex vivo tumor sections. Results:The change in slope of the 111 In-anti-γH2AX-TAT to 177 Lu signal between days 5 and 7 was found to be highly predictive of survival (r = 0.955, P < 0.0001). This pivotal timeframe was investigated further in vitro: clonogenic survival correlated with the number of γH2AX foci at day 6 (r = -0.995, P < 0.0005). While there was evidence of continuously low levels of apoptosis, delayed induction of senescence in vitro appeared to better account for the γH2AX response to 177 Lu. The induction of senescence was further investigated by ex vivo analysis and corresponded with sustained retention of 177 Lu within tumor regions. Conclusions: Dual isotope SPECT imaging can provide individualized tumor dose-responses that can be used to predict lutetium-177 treatment efficacy. This bio-dosimeter metric appears to be dependent upon the extent of senescence induction and suggests an integral role that senescence plays in lutetium-177 treatment efficacy.

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“…The future of Auger electronemitting radiopharmaceuticals was also discussed in a commentary [13]. Finally, reviews covered studies using gold nanoparticles [14], drug and MRT combination therapies [15,16], subcellular localisation methodologies for radionuclides [17], biomarkers of therapy response [18], healthy tissue toxicity [19,20], and extranuclear targets, bystander and systemic responses [21].…”

mentioning

confidence: 99%