Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system x radiotracer, [F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC.

Intratumoral Distribution of [Lu]Lu-PSMA-617 Over Time and in Relation to Diagnostic Tracers in Animal Models of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a target for diagnostic positron emission tomography (PET)-tracers and radiopharmaceutical therapy (RPT), for example, [Lu]Lu-PSMA-617, in prostate cancer. This autoradiography study investigates [Lu]Lu-PSMA-617 intratumoral distribution over time, compared with PSMA expression, proliferation (Ki67), and [Ga]Ga-PSMA-11, [F]F-PSMA-1007, [F]-fluorodeoxyglucose, and [F]-fluorocholine distribution. Mice with LNCaP, 22Rv1, or PC-3 PIP xenografts got [Lu]Lu-PSMA-617 i.

Evaluation of superficial xenograft volume estimation by ultrasound and caliper against MRI in a longitudinal pre-clinical radiotherapeutic setting.

Background: Accurate tumor volume estimation is important for evaluating the response to radionuclide therapy and external beam radiotherapy as well as to other pharmaceuticals. A common method for monitoring the growth of subcutaneous tumors in pre-clinical models and assessing the treatment response is to measure the tumor length and width by external calipers to estimate its volume. This procedure relies on an assumption of a spheroidal tumor shape wherein the tumor depth equals the width and can yield considerably inaccuracies.

Investigating Ras homolog gene family member C (RhoC) and Ki67 expression following external beam radiation therapy show increased RhoC expression in relapsing prostate cancer xenografts.

Ras homolog gene family member C (RhoC) is a GTPase involved in cell migration, implicated in epithelial-mesenchymal transition and treatment resistance and metastasis of cancer. For example, RhoC has been shown to be involved in resistance to radiation in cervical carcinoma. Here, the effect of X-ray irradiation on RhoC expression in prostate cancer (PCa) xenografts was investigated in both xenografts in regression and relapse.

Hematological and renal toxicity in mice after three cycles of high activity [Lu]Lu-PSMA-617 with or without human α-microglobulin.

Radioligand therapy with [Lu]Lu-PSMA-617 can be used to prolong life and reduce tumor burden in terminally ill castration resistant prostate cancer patients. Still, accumulation in healthy tissue limits the activity that can be administered. Therefore, fractionated therapy is used to lower toxicity.

Imaging the master regulator of the antioxidant response in non-small cell lung cancer with positron emission tomography.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. The cystine/glutamate antiporter, system x, is one of the >200 cytoprotective proteins controlled by NRF2, which can be non-invasively imaged by ()-4-(3-F-fluoropropyl)-l-glutamate ([F]FSPG) positron emission tomography (PET). Through genetic and pharmacologic manipulation, we show that [F]FSPG provides a sensitive and specific marker of NRF2 activation in advanced preclinical models of NSCLC.

Imaging the Tumor Antioxidant Response with [F]FSPG PET.

(4S)-4-(3-[F]Fluoropropyl)-L-glutamic acid ([F]FSPG) is a flourine-18 labeled glutamate analog that enables the noninvasive in vivo imaging of cellular redox status. [F]FSPG is transported across the cell membrane by the cystine/glutamate antiporter, system x, whose expression is upregulated in multiple cancer types. The requirement of cystine for the biosynthesis of glutathione, a major antioxidant, connects [F]FSPG tissue retention to the intracellular redox response via system x activity.

Tumor Control Probability and Small-Scale Monte Carlo Dosimetry: Effects of Heterogenous Intratumoral Activity Distribution in Radiopharmaceutical Therapy.

In radiopharmaceutical therapy, intratumoral uptake of radioactivity usually leads to heterogeneous absorbed dose distribution. The likelihood of treatment success can be estimated with the tumor control probability (TCP), which requires accurate dosimetry, estimating the absorbed dose rate per unit activity to individual tumor cells. Xenograft cryosections of the prostate cancer cell line LNCaP treated with [Lu]Lu-PSMA-617 were evaluated with digital autoradiography and stained with hematoxylin and eosin.

Evaluation of enhanced permeability effect and different linear energy transfer of radionuclides in a prostate cancer xenograft model.

We have previously investigated the biodistribution and therapy effect of a humanized monoclonal antibody targeting free prostate-specific antigen (fPSA) intended for theranostics of hormone-refractory prostate cancer. In the present study, we evaluated the off-target effect and different linear energy transfer (LET) radionuclides without the effect of PSA targeting by using an antibody with the same scaffold as previously used immunoconjugates but with random, non-specific, antigen binding region. This allows us to identify alterations generated by specific targeting and those related to passive bystander effects, such as enhanced permeability and retention (EPR).

Small-scale dosimetry for alpha particle Am source cell irradiation and estimation of γ-H2AX foci distribution in prostate cancer cell line PC3.

Background: The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets.

Hematological Toxicity in Mice after High Activity Injections of Lu-PSMA-617.

Prostate cancer (PC) is one of the most common malignancies affecting men, with poor prognosis after progression to metastatic castration-resistant prostate cancer (mCRPC). Radioligand therapy (RLT) targeting the overexpressed PSMA on PC cells, with, e.g.

Humanization, Radiolabeling and Biodistribution Studies of an IgG-Type Antibody Targeting Uncomplexed PSA for Theranostic Applications.

Metastatic castration-resistant prostate cancer is today incurable. Conventional imaging methods have limited detection, affecting their ability to give an accurate outcome prognosis, and current therapies for metastatic prostate cancer are insufficient. This inevitably leads to patients relapsing with castration-resistant prostate cancer.

Kidney Protection with the Radical Scavenger α-Microglobulin (A1M) during Peptide Receptor Radionuclide and Radioligand Therapy.

α-Microglobulin (A1M) is an antioxidant found in all vertebrates, including humans. It has enzymatic reductase activity and can scavenge radicals and bind free heme groups. Infused recombinant A1M accumulates in the kidneys and has therefore been successful in protecting kidney injuries in different animal models.

A Conjugation Strategy to Modulate Antigen Binding and FcRn Interaction Leads to Improved Tumor Targeting and Radioimmunotherapy Efficacy with an Antibody Targeting Prostate-Specific Antigen.

Background: The humanized monoclonal antibody (mAb) hu5A10 specifically targets and internalizes prostate cancer cells by binding to prostate specific antigen (PSA). Preclinical evaluations have shown that hu5A10 is an excellent vehicle for prostate cancer (PCa) radiotheranostics. We studied the impact of different chelates and conjugation ratios on hu5A10's target affinity, neonatal fc-receptor interaction on in vivo targeting efficacy, and possible enhanced therapeutic efficacy.

Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α-Microglobulin (A1M), Including Kidney Damage Assessment Using Tc-MAG3 Imaging.

Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α-microglobulin (A1M) together with 177-Lutetium (Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity.

Preclinical efficacy of hK2 targeted [Lu]hu11B6 for prostate cancer theranostics.

Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease.

Radioimmunotherapy for Prostate Cancer--Current Status and Future Possibilities.

Prostate cancer (PCa) is one of the most common cancers in men and is the second leading cause of cancer-related deaths in the USA. In the United States, it is the second most frequently diagnosed cancer after skin cancer, and in Europe it is number one. According to the American Cancer Society, approximately 221,000 men in the United States would be diagnosed with PCa during 2015, and approximately 28,000 would die of the disease.

Radiosensitivity of Prostate Cancer Cell Lines for Irradiation from Beta Particle-emitting Radionuclide ¹⁷⁷Lu Compared to Alpha Particles and Gamma Rays.

Aim: The purpose of the present study was to investigate the radiosensitivity of the prostate cancer cell lines LNCaP, DU145, and PC3 when irradiated with beta particles emitted from (177)Lu, and to compare the effect with irradiation using alpha particles or gamma rays.

Materials And Methods: Cells were irradiated with beta particles emitted from (177)Lu, alpha particles from (241)Am, or gamma rays from (137)Cs. A non-specific polyclonal antibody was labeled with (177)Lu and used to irradiate cells in suspension with beta particles.

Preclinical imaging of kallikrein-related peptidase 2 (hK2) in prostate cancer with a (111)In-radiolabelled monoclonal antibody, 11B6.

Background: Prostate cancer is a leading cause of death in the male population of the western world. Human kallikrein-related peptidase 2 (hK2) is abundantly expressed in malignant prostatic tissue, and its gene, KLK2, is regulated by the androgen receptor. 11B6 is a murine IgG1 monoclonal antibody directed against free human hK2.

Intratherapeutic biokinetic measurements, dosimetry parameter estimates, and monitoring of treatment efficacy using cerenkov luminescence imaging in preclinical radionuclide therapy.

Unlabelled: In recent years, there has been increasing interest in noninvasive Cerenkov luminescence imaging (CLI) of in vivo radionuclide distribution in small animals, a method proven to be a high-throughput modality for confirmation of tracer uptake. 11B6 is an IgG1 monoclonal antibody that is specific to free human kallikrein-related peptidase 2, an antigen abundant in malignant prostatic tissue. Free human kallikrein-related peptidase 2 was targeted in prostate cancer xenografts using (177)Lu-labeled 11B6 in either murine or humanized forms for radionuclide therapy.

Radiolabeled antibodies in prostate cancer: a case study showing the effect of host immunity on antibody bio-distribution.

Objectives: Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of (111)In-DTPA-5A10, which targets free prostate specific antigen (fPSA), in two animal models.

Preclinical evaluation of (111)In-DTPA-INCA-X anti-Ku70/Ku80 monoclonal antibody in prostate cancer.

The aim of this investigation was to assess the Ku70/Ku80 complex as a potential target for antibody imaging of prostate cancer. We evaluated the in vivo and ex vivo tumor targeting and biodistribution of the (111)In-labeled human internalizing antibody, INCA-X ((111)In-DTPA-INCA-X antibody), in NMRI-nude mice bearing human PC-3, PC-3M-Lu2 or DU145 xenografts. DTPA-conjugated, non-labeled antibody was pre-administered at different time-points followed by a single intravenous injection of (111)In-DTPA-INCA-X.