Ny prostatacancerbehandling med Nobelkoppling

11 tyska forskare från 9 olika institut har genomfört oerhört viktig forskning för prostatacancerdrabbade.

Forskarnas studier är efterlängtade av världens behandlande cancerläkare,specifikt prostatainriktade sådana.

Det handlar om en förhållandevis tämligen ny typ av behandlingsform för spridd prostatacancer,nämligen tillförsel av en radioaktivmärkt molekyl som söker upp prostatacancerceller inne i kroppen och via dess lågintensiva strålning dödar cancercellerna.

Branschtidningen Dagens Medicin skrev förra året en artikel om tekniken.  

Tunga bevis för nytta med omtalad prostatabehandling

"Den nya behandlingen, med namnet lutetium-177-PSMA-617, består av en antikropp riktad mot ett prostataprotein som uttrycks av tumörerna hos runt 80 procent av patienterna med spridd prostatacancer. Till antikroppen är det kopplat en särskild isotop av grundämnet lutetium, som ger en stråleffekt till tumörerna och deras omgivning. Behandlingen och dess lovande effekt har de senaste åren fått stor uppmärksamhet, inte minst bland patienter. Vissa patienter har lagt ut uppemot 1 miljon kronor ur egen ficka för att få radioaktivt lutetium som erbjudits på utländska kliniker.Eftersom behandlingen inte varit vetenskapligt etablerad eller ens regulatoriskt godkänd har svensk sjukvård inte kunna erbjuda den i klinisk rutin utan bara till en del patienter inom ramen av kliniska studier."

 

Finländska cancersjukhuset Docrates var tidiga användare av en ursprunglig typ av tekniken.Finländsk lagstiftning möjliggjorde via specialtillstånd behandling med tekniken fast det fattades forskning som visade verifierad fakta.

Patienter som var berörda hade redan fått sin dödsdom så dessa var naturligtvis högst motiverade att testa denna behandlingsform som en sista utväg.Sverige har inte godkänt denna behandlingsform fast patientgrupper legat på för att förändra det.Likaså har andra länder agerat.Man har velat se omfattande studier som bekräftar att nyttan överstiger riskerna med att använda sig av ett kontroversiellt ämne som ett radioaktivt grundämne får sägas vara.

Men..*trumvirvel* nu har dessa tyska forskare gett världen de bevis som krävs för att verifiera nytta kontra risk.

De skriver själva att amerikanska FDA väntas godkänna tekniken inom kort.Forskarna har som jag tolkar det lyckats utveckla en hybridmodell som gör att strålningsexponering till frisk omkringliggande vävnad och organ reducerats till ett minimum.Där ligger storheten i dessa studier.Utan att veta till 100% tror jag att stötestenen för ett godkännande har varit just det,den överhängande risken att strålningen gjort för stor skada på omkringliggande vävnad och organ. >>Patienten överlevde sin cancer men dog av komplikationer till följd av behandlingen.<<

För att komma tillrätta med den "bieffekten" krävdes studier på allra högsta nivå och naturligtvis även teknisk utrustning på samma höga nivå. Ni förstår vart jag är på väg?

Ett flertal av de medverkande 9 instituten har tydlig Stefan W. Hell koppling.

Lab of Nobel Price winner purchases HoloMonitor

June 8, 2016

The Department of Optical Nanoscopy (Prof. Stefan W. Hell) at the German Cancer Research Center (DKFZ) in Heidelberg recently ordered a motorized HoloMonitor M4. Professor Hell was awarded the Nobel Prize in Chemistry in 2014 for his pioneering work in the field of super-resolution fluorescence microscopy. The customer list price of the ordered unit is 350 000 SEK.

“It is a great honor for us to have the research team of a Nobel Prize winning scientist added to our growing list of customers, selecting our HoloMonitor microscope for their research needs”, said CEO Peter Egelberg.

Studiens komplexitet och sedermera dess resultat bär prägel av ett överinseende av Maestro himself.

Hell blev filosofie doktor 1990 vid Heidelbergs universitet. Han är forskningsledare vid Max Planck-Institut für biophysikalische Chemie i Göttingen och chef för Deutsches Krebsforschungszentrum (DKFZ) i Heidelberg. 

Kolla forskarnas respektive institut och jämför så ser ni att Mr Hell´s ande svävar tydligt över flera av dessa.

 

A New Class of PSMA-617-Based Hybrid Molecules for Preoperative Imaging and Intraoperative Fluorescence Navigation of Prostate Cancer

by

Ann-Christin Eder

^1,2,3,*,

Jessica Matthias

⁴,

Martin Schäfer

¹,

Jana Schmidt

¹,

Nils Steinacker

^2,3,

Ulrike Bauder-Wüst

¹,

Lisa-Charlotte Domogalla

^2,3,

Mareike Roscher

¹,

Uwe Haberkorn

^5,6,

Matthias Eder

^2,3,† and

Klaus Kopka

^1,7,8,9,†

¹

Department of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

²

Department of Nuclear Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany

³

Department of Radiopharmaceutical Development, German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany and German Cancer Research Center, 69120 Heidelberg, Germany

⁴

Department of Optical Nanoscopy, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany

⁵

Department of Nuclear Medicine, Heidelberg University Hospital, 69120 Heidelberg, Germany

⁶

Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

⁷

Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany

⁸

German Cancer Consortium (DKTK), Partner Site Dresden, 01328 Dresden, Germany

⁹

School of Science, Faculty of Chemistry and Food Chemistry, Technical University Dresden, 01069 Dresden, Germany

 

Abstract

The development of PSMA-targeting low-molecular-weight hybrid molecules aims at advancing preoperative imaging and accurate intraoperative fluorescence guidance for improved diagnosis and therapy of prostate cancer. In hybrid probe design, the major challenge is the introduction of a bulky dye to peptidomimetic core structures without affecting tumor-targeting properties and pharmacokinetic profiles. This study developed a novel class of PSMA-targeting hybrid molecules based on the clinically established theranostic agent PSMA-617. The fluorescent dye-bearing candidates of the strategically designed molecule library were evaluated in in vitro assays based on their PSMA-binding affinity and internalization properties to identify the most favorable hybrid molecule composition for the installation of a bulky dye. The library’s best candidate was realized with IRDye800CW providing the lead compound. Glu-urea-Lys-2-Nal-Chx-Lys(IRDye800CW)-DOTA (PSMA-927) was investigated in an in vivo proof-of-concept study, with compelling performance in organ distribution studies, PET/MRI and optical imaging, and with a strong PSMA-specific tumor uptake comparable to that of PSMA-617. This study provides valuable insights about the design of PSMA-targeting low-molecular-weight hybrid molecules, which enable further advances in the field of peptidomimetic hybrid molecule development. 

 

1. Introduction

The development of the theranostic agent PSMA-617, a prostate-specific membrane antigen (PSMA) inhibitor with highly specific tumor enhancement and superior pharmacokinetics, has remarkably advanced diagnostics and therapy of prostate cancer. PSMA-617 can be labeled with positron-emitters (e.g., ⁶⁸Ga) for imaging or with radionuclides suitable for therapy (e.g., ¹⁷⁷Lu, ²²⁵Ac) of recurrent prostate carcinoma. In particular, the rapid renal elimination profile of PSMA-617 renders the molecule advantageous for therapeutic approaches, as its enrichment in non-malignant tissue, and therefore the associated radiation exposure, is reduced to a minimum.

Efficacy, safety, and quality of life after [¹⁷⁷Lu]Lu-PSMA-617 therapy have been evaluated in a phase II clinical trial. At twelve weeks after the first dose, half of the patients experienced a prostate-specific antigen (PSA) decline greater than 50%, whereas for 27% of the patients, the PSA decline was even greater than 80%. The currently most advanced clinical trial is a recently completed phase III study (VISION) comprising 831 patients. Published data suggest that [¹⁷⁷Lu]Lu-PSMA-617 significantly improves overall survival while the treatment regimen is very well-tolerated. Hence, the FDA approval of radioligand therapy with [¹⁷⁷Lu]Lu-PSMA-617 is expected shortly. Due to its outstanding clinical performance and its favorable pharmacokinetic profile, PSMA-617 represents an ideal core structure for hybrid ligand development in the field of prostate cancer.

In the case of localized and locally advanced prostate cancer, radical prostatectomy with lymph node dissection and lymphadenectomy is an established curative strategy. Preoperatively, the identification of primary tumors and metastases can be performed precisely with PSMA-targeting diagnostic radiopharmaceuticals by PET/CT imaging. However, the accurate intraoperative localization and delineation of tumor margins or lymph node metastases is still a major challenge in oncological surgery in general. For prostate carcinoma, the established workaround is a template-based removal of nonpathological lymph nodes with the drawback of increased morbidity. Additionally, there is an enhanced risk of residual tumorous structures. Targeted hybrid molecules comprising both radio- and fluorescent label promise to overcome these limitations by supporting pre- as well as intraoperative navigation. The radioactive label allows for preoperative cancer staging and surgery planning by noninvasive imaging (e.g., PET/CT), and the fluorescent label subsequently provides visual intraoperative guidance.

For clinical applications, low-molecular-weight peptidomimetics provide the ideal molecular format. Due to fast clearance from nontarget organs and high tumor penetration and retention, such molecules yield clear imaging contrasts at early time points after injection, simplifying clinical protocols. Recently, the first PSMA-targeting peptidomimetic low-molecular-weight hybrid agents have been developed. With the research field still in its infancy, the first clinical application of the PSMA-11-derived peptidomimetic PSMA-targeting molecule PSMA-914 already highlights the great future potential of targeted hybrid agents in the surgical treatment of prostate cancer patients and emphasizes the urgent need for further preclinical development and clinical studies.

From a preclinical perspective, the development of novel hybrid molecules based on preceding generations allows to further improve the molecules’ properties (tumor targeting, pharmacokinetics) by benefitting from previously gained knowledge, in particular about structure–activity relationships. Here, the major challenge in hybrid probe design is to preserve a fast pharmacokinetic profile (fast distribution and clearance rate) as well as high and specific tumor targeting properties when introducing a bulky dye to the comparatively small low-molecular-weight peptidomimetic.

This preclinical proof-of-concept study aimed at identifying favorable molecule compositions for the installation of bulky dyes to further fuel the field of hybrid probe development. We present a novel class of PSMA-targeting hybrid molecules based on the clinically established theranostic agent PSMA-617. Introducing the dual-label to the core structure via a lysine branch resulted in a strategically designed molecule library.

In the first step, the ideal hybrid molecule composition (dye position in the molecule, additional introduction of glutamic acid spacer moieties) was identified via its PSMA-binding properties and internalization profiles. In the second step, the clinically relevant IRDye800CW was introduced to the library’s best candidate to form the lead compound of this study. IRDye800CW was chosen over its clinically approved alternative indocyanine green, as the latter is prone to human serum albumin binding, which tremendously slows down pharmacokinetics. In the third step, the lead compound’s tumor uptake and pharmacokinetic properties were determined.

 

För att knyta ihop säcken "studier på allra högsta nivå och teknisk utrustning på samma höga nivå" kommer här det ni alla väntat på : användande av HoloMonitor.

To assess potential cytotoxic effects of PSMA-927, LNCaP cell proliferation was monitored by holographic time-lapse imaging during constant compound exposure for 48 h (Figure 3A, Supplemental Movie S1 and Movie S2). Analysis of cell count (Figure 3B), confluency (Figure 3C), frequency of cell division (Figure 3D), and cell cycle length (Figure 3E) did not reveal any evidence of cytotoxicity. We attributed the slightly reduced cell division frequency to the biological variation that was expected for this in vitro assay, as it was not reflected in a decreased cell count. Nevertheless, the data are in good agreement with previous cytotoxicity studies of STED-compatible hybrid PSMA-inhibitors [19].

 

Figure 3. Holographic time-lapse imaging of LNCaP cell proliferation under compound exposure. LNCaP cell proliferation was followed for a total period of 48 h in the absence of (control, cyan, experiments n = 38, tracked cells n = 33,031, divisions n = 9157, Supplemental Movie S1) and in the constant presence of 100 nmol/L PSMA-927 (hybrid molecule, red, experiments n = 25, tracked cells n = 35,804, divisions n = 8421) via holographic time-lapse cytometry. (A) Holographic image sequences of a cell division in the presence of compound. Dividing cells rounded up and could be distinguished from nondividing cells by height (color-coded); scale bar, 50 μm. A corresponding time-lapse movie (Supplemental Movie S2) is supplied. (B) Normalized cell count (average p-value 0.235 ± 0.227) and (C) normalized confluency (average p-value 0.546 ± 0.251) of untreated and treated LNCaP cells. (D) Frequency of cell division and (E) cell cycle length of untreated and treated LNCaP cells. Significance: *** p < 0.001; ns, no significant differences.

 

These results were supported by confocal imaging experiments. Both live- and fixed-cell data confirmed PSMA-specific internalization and an increasing compound accumulation over time. Strikingly, PSMA-927 performed significantly better in terms of photostability under live-cell imaging conditions, further qualifying it for intraoperative navigation. Additionally, cytotoxicity of the compound could be excluded by in vitro holographic time-lapse imaging.

4. Materials and Methods

4.5. Cytotoxicity Study

Potential cytotoxicity of PSMA-927 was assessed by analyzing the frequency of LNCaP cell division and the length of the LNCaP cell cycle via holographic time-lapse imaging. Cells were seeded in lumox^® 24-well plates (Sarstedt, Nümbrecht, Germany) 48 h prior to the experiment and kept at 37 °C and 5% CO₂. Imaging was performed with a HoloMonitor^® M4 cytometer (PHI AB, Lund, Schweden) for a total period of 48 h at 37 °C and 5% CO₂ with 15 min between image captures. Cell proliferation was followed in absence and in presence of 100 nmol/L PSMA-927. Data analysis was performed with the AppSuite software including cell segmentation, tracking of cells, identification of dividing cells, confluency measurement, and cell counting.

Kompletterande information

Svensk studie som berör PSMA-617 och dess biverkningar

Ny riktad strålterapi för metastaserande prostatacancer ger hopp

 

 

Min kommentar 

Det ska sägas direkt att jag INTE har några konkreta bevis för att denna studie har "supervisats" av Nobelpristagaren Stefan W. Hell.Dock är tecknen många att så ändå är fallet.Framkommer det i ett senare skede att Mr Hell haft ett/flera fingrar med i denna forskning ska naturligtvis PHI uppmärksamma detta.

PR-värdet är mer än hyggligt.

Stort glädjeämne är att världens alla patienter med spridd prostatacancer snart har en efterlängtad och godkänd behandlingsform att se fram mot.

Att PHI via sitt eminenta system HoloMonitor bidragit till dess tillkomst känns stort.

                                                 Mvh the99

 

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