Peptide Receptor Radionuclide Therapy: Looking Back, Looking Forward

Feijtel, Danny; Jong, Marion de; Nonnekens, Julie

doi:10.2174/1568026620666200226104652

Cited by 29 publications

(23 citation statements)

References 89 publications

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“…Many different angles for improvement of therapeutic efficacy are currently being investigated as NETs become more prevalent and standard of care treatment is still not curative 6 , 39 , 50 . As we have shown that SST 2 expression levels can influence cellular therapy effects, it is an interesting concept to stimulate SST 2 expression to improve therapeutic outcome.…”

Section: Discussionmentioning

confidence: 99%

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Feijtel¹,

Doeswijk²,

Verkaik³

et al. 2021

Theranostics

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Patients with neuroendocrine tumors (NETs) can be treated with peptide receptor radionuclide therapy (PRRT). Here, the somatostatin analogue octreotate radiolabeled with lutetium-177 is targeted to NET cells by binding to the somatostatin receptor subtype 2 (SST 2 ). During radioactive decay, DNA damage is induced, leading to NET cell death. Although the therapy proves to be effective, mortality rates remain high. To appropriately select more optimal treatment strategies, it is essential to first better understand the radiobiological responses of tumor cells to PRRT. Methods: We analyzed PRRT induced radiobiological responses in SST 2 expressing cells and xenografted mice using SPECT/MRI scanning and histological and molecular analyses. We measured [ 177 Lu]Lu-DOTA-TATE uptake and performed analyses to visualize induction of DNA damage, cell death and other cellular characteristics. Results: The highest accumulation of radioactivity was measured in the tumor and kidneys. PRRT induced DNA damage signaling and repair in a time-dependent manner. We observed intra-tumor heterogeneity of DNA damage and apoptosis, which was not attributed to proliferation or bioavailability. We found a strong correlation between high DNA damage levels and high SST 2 expression. PRRT elicited a different therapeutic response between models with different SST 2 expression levels. Heterogeneous SST 2 expression levels were also confirmed in patient NETs. Conclusion: Heterogeneous SST 2 expression levels within NETs cause differentially induced DNA damage levels, influence recurrent tumor phenotypes and impact the therapeutic response in different models and potentially in patients. Our results contribute to a better understanding of PRRT effects, which might impact future therapeutic outcome of NET patients.

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Section: Discussionmentioning

confidence: 99%

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Feijtel¹,

Doeswijk²,

Verkaik³

et al. 2021

Theranostics

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“…These features give important implications for our understanding of MRT radiobiology and future research directions. Apart from investigating different radionuclides, the current search for improvements includes testing other peptides or antibodies, identifying novel tumor target molecules and using combination treatments to enhance therapy effect [67]. Visualization of DNA damage induction patterns of beta-emitters, alpha-emitters and Auger electrons, ordered (from left to right) by decreasing penetration range and increasing complexity of induced DNA damage.…”

Section: Molecular Radionuclide Therapy (Mrt)mentioning

confidence: 99%

Section: Dna Damage-inducing Therapiesmentioning

confidence: 99%

DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

Reuvers

Kanaar

Nonnekens

2020

Cancers

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DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.

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“…This emphasizes the need to further optimize [ 177 Lu]Lu-DOTA-TATE radionuclide therapy to further improve efficacy while reducing toxicity. This includes improved dosimetry hand in hand with a deep biological evaluation of superior radionuclides, improved SST 2 ligands, increased SST 2 levels, the role of tumor microenvironment, and combinations with immunotherapy, targeted therapy or DNA modulating agents, as well as predictive markers for improved patient selection and treatment follow-up [24,44,45,[89][90][91].…”

Section: Radiobiologymentioning

confidence: 99%

EANM position paper on the role of radiobiology in nuclear medicine

Aerts

Eberlein

Holm

et al. 2021

Eur J Nucl Med Mol Imaging

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Executive SummaryWith an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.

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Peptide Receptor Radionuclide Therapy: Looking Back, Looking Forward

Cited by 29 publications

References 89 publications

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response

DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

EANM position paper on the role of radiobiology in nuclear medicine

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