5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      From the Magic Bullet to Theragnostics: Certitudes and Hypotheses, Trying to Optimize the Somatostatin Model

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Simple Summary

          In oncology, the hypothetical “perfect magic bullet” should have a specific target on tumor cells which allows one to target only the tumor, in the absence of uptake in normal and/or non-neoplastic cells. Theragnostics is a strategy that strictly combines diagnosis and therapy, which creates the conditions for an “a priori” definition of an effective therapeutic effect. The most complete theragnostic and “magic bullet” experiences in clinical practice are those associated with radioiodine and somatostatin model. In this paper, we analyze whether it could be possible to improve present clinical results, further extending the survival of a wider number of patients, expanding the recruitment criteria to other types of pathology, and improving the quality of life. The ultimate goal is to transform the theragnostic strategy based on the somatostatin model into a curative therapy in the highest possible number of patients.

          Abstract

          The first “theragnostic model”, that of radioiodine, was first applied both in diagnosis and therapy in the 1940s. Since then, many other theragnostic models have been introduced into clinical practice. To bring about the closest pharmacokinetic connection, the radiocompound used for diagnosis and therapy should be the same, although at present this is rarely applicable. Today, a widely applied and effective model is also the “DOTA-Ga-68/Lu-177”, used with success in neuroendocrine tumors (NET). In this paper, we analyze the necessary steps from the in vitro evaluation of a target to the choice of radionuclide and chelate for therapy up to in vivo transition and clinical application of most employed radiocompounds used for theragnostic purposes. Possible future applications and strategies of theragnostic models are also highlighted.

          Related collections

          Most cited references45

          • Record: found
          • Abstract: found
          • Article: not found

          Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors.

          Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ((177)Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either (177)Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ((177)Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the (177)Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the (177)Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the (177)Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the (177)Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with (177)Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the (177)Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).
            Bookmark
            • Record: found
            • Abstract: not found
            • Article: not found

            The path to personalized medicine.

              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated.

              Ionizing radiation can reduce tumor growth outside the field of radiation, known as the abscopal effect. Although it has been reported in multiple malignancies, the abscopal effect remains a rare and poorly understood event. Ionizing radiation generates inflammatory signals and, in principle, could provide both tumor-specific antigens from dying cells and maturation stimuli that are necessary for dendritic cells' activation of tumor-specific T cells. We therefore tested the hypothesis that the abscopal effect elicited by radiation is immune mediated. This was directly tested by enhancing the number of available dendritic cells using the growth factor Flt3-Ligand (Flt3-L). Mice bearing a syngeneic mammary carcinoma, 67NR, in both flanks were treated with Flt3-L daily for 10 days after local radiation therapy (RT) to only 1 of the 2 tumors at a single dose of 2 or 6 Gy. The second nonirradiated tumor was used as indicator of the abscopal effect. Data were analyzed using repeated measures regression. RT alone led to growth delay exclusively of the irradiated 67NR tumor, as expected. Surprisingly, growth of the nonirradiated tumor was also impaired by the combination of RT and Flt3-L. As control, Flt3-L had no effect without RT. Importantly, the abscopal effect was shown to be tumor specific, because growth of a nonirradiated A20 lymphoma in the same mice containing a treated 67NR tumor was not affected. Moreover, no growth delay of nonirradiated 67NR tumors was observed when T cell deficient (nude) mice were treated with RT plus Flt3-L. These results demonstrate that the abscopal effect is in part immune mediated and that T cells are required to mediate distant tumor inhibition induced by radiation.
                Bookmark

                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                12 July 2021
                July 2021
                : 13
                : 14
                : 3474
                Affiliations
                [1 ]Nuclear Medicine Service, Check-Up Polydiagnostic Center, 84131 Salerno, Italy; danilo.distasio@ 123456check-up.net
                [2 ]Nuclear Medicine Service, Ios and Coleman Medicina Futura Medical Center, 80011 Acerra, Italy; pbuonomano90@ 123456gmail.com
                [3 ]Nuclear Medicine Division, European Institute of Oncology—IRCCS, 20141 Milano, Italy; laura.travaini@ 123456ieo.it (L.L.T.); chiara.grana@ 123456ieo.it (C.M.G.)
                [4 ]Section Health and Development, Interuniversity Research Center for Sustainability (CIRPS), 00038 Rome, Italy
                Author notes
                [* ]Correspondence: mansi.luigi@ 123456libero.it ; Tel.: +39-3280024554
                Article
                cancers-13-03474
                10.3390/cancers13143474
                8305798
                34298688
                5f18509b-1037-4448-96b9-7271d8a9b1f1
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 20 May 2021
                : 09 July 2021
                Categories
                Review

                theragnostics,magic bullet,somatostatin,radioiodine,dota,radionuclide therapy,prrt,nets

                Comments

                Comment on this article