PSMA radioligand therapy for solid tumors other than prostate cancer: background, opportunities, challenges, and first clinical reports.

In the past decade, a growing body of literature has reported promising results for prostate-specific membrane antigen (PSMA)-targeted radionuclide imaging and therapy in prostate cancer. First clinical studies evaluating the efficacy of [177Lu]Lu-PSMA radioligand therapy (PSMA-RLT) demonstrated favorable results in prostate cancer patients. [177Lu]Lu-PSMA is generally well tolerated due to its limited side effects. While PSMA is highly overexpressed in prostate cancer cells, varying degrees of PSMA expression have been reported in other malignancies as well, particularly in the tumor-associated neovasculature. Hence, it is anticipated that PSMA-RLT could be explored for other solid cancers. Here, we describe the current knowledge of PSMA expression in other solid cancers and define a perspective towards broader clinical implementation of PSMA-RLT. This review focuses specifically on salivary gland cancer, glioblastoma, thyroid cancer, renal cell carcinoma, hepatocellular carcinoma, lung cancer, and breast cancer. An overview of the (pre)clinical data on PSMA immunohistochemistry and PSMA PET/CT imaging is provided and summarized. Furthermore, the first clinical reports of non-prostate cancer patients treated with PSMA-RLT are described.

Bone tumor-targeted delivery of theranostic 195mPt-bisphosphonate complexes promotes killing of metastatic tumor cells.

Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum (195mPt) is a rich source of low-energy Auger electrons, which kills tumor cells by damaging DNA. Auger electrons damage cells over a very short range. Consequently, 195mPt-based radiopharmaceuticals should be targeted toward â€‹tumors to maximize radiotherapeutic efficacy and minimize Pt-based systemic toxicity. Herein, we show that systemically administered radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes specifically accumulate in intratibial bone metastatic lesions in mice. The 195mPt-BP complexes accumulate 7.3-fold more effectively in bone 7 days after systemic delivery compared to 195mPt-cisplatin lacking bone-targeting bisphosphonate ligands. Therapeutically, 195mPt-BP treatment causes 4.5-fold more γ-H2AX formation, a biomarker for DNA damage in metastatic tumor cells compared to 195mPt-cisplatin. We show that systemically administered 195mPt-BP is radiotherapeutically active, as evidenced by an 11-fold increased DNA damage in metastatic tumor cells compared to non-radioactive Pt-BP controls. Moreover, apoptosis in metastatic tumor cells is enhanced more than 3.4-fold upon systemic administration of 195mPt-BP vs. radioactive 195mPt-cisplatin or non-radioactive Pt-BP controls. These results provide the first preclinical evidence for specific accumulation and strong radiotherapeutic activity of 195mPt-BP in bone metastatic lesions, which offers new avenues of research on radiotherapeutic killing of tumor cells in bone metastases by Auger electrons.

Radioimmunotherapy prevents local recurrence of colonic cancer in an experimental model.

BACKGROUND: Radioimmunotherapy (RIT) is suitable for the treatment of microscopic residual disease and might therefore have an adjuvant role after colonic cancer surgery. METHODS: An anastomosis was constructed in male Wag/Rij rats after intraluminal injection of 2 x 10(6) CC531 tumour cells. The biodistribution of (111)In-labelled MG1 monoclonal antibody was assessed after intraperitoneal administration. The therapeutic efficacy of (177)Lu-labelled MG1 (74 MBq per rat), administered on the day of surgery (D0, n = 13) or 5 days later (D5, n = 13), was compared with that of carrier only (n = 13). The primary endpoint was perianastomotic tumour growth 28 days after surgery. RESULTS: (111)In-labelled MG1 preferentially accumulated in perianastomotic CC531 tumours. RIT resulted in a transient reduction in bodyweight in both treatment groups compared with controls, but there were no other signs of clinical discomfort. No macroscopic or microscopic perianastomotic tumour growth was found in eight of 11 animals in the D0 group and 11 of 13 in the D5 group, whereas 11 of 13 controls had macroscopic tumour (P = 0.011 and P = 0.001 respectively). CONCLUSION: This study suggests that RIT may be an effective adjuvant treatment for preventing local recurrence after resection of colonic cancer.

The in vivo fate of 225Ac daughter nuclides using polymersomes as a model carrier.

Increasing attention is given to personalized tumour therapy, where α-emitters can potentially play an important role. Alpha particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon the emission of an α particle the daughter nuclide experiences a recoil energy large enough to ensure decoupling from any chemical bond. These 'free' daughter nuclides are no longer targeted to the tumour and can accumulate in normal tissue. In this paper, we used polymersomes as model carrier to evaluate the retention of recoiling daughters of 225Ac in vivo, and assessed their suitability as therapeutic agents. Vesicles containing 225Ac were injected intravenously in healthy mice, and intratumourally in tumour-bearing mice, and the relocation of free 213Bi was assessed in different organs upon the injection [225Ac]Ac-polymersomes. The therapeutic effect of 225Ac-containing vesicles was studied upon intratumoural injection, where treatment groups experienced no tumour-related deaths over a 115 day period. While polymersomes containing 225Ac could be suitable agents for long-term irradiation of tumours without causing significant renal toxicity, there is still a significant re-distribution of daughter nuclides throughout the body, signifying the importance of careful evaluation of the effect of daughter nuclides in targeted alpha therapy.

Tumor-receptor imaging in breast cancer: a tool for patient selection and response monitoring.

Breast cancer is a heterogeneous disease that can be subdivided into different groups, based on gene expression profiles or clinicopathological characteristics such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression. The expression of these receptors has both prognostic and predictive value. To improve breast cancer treatment, accurate methods for patient selection and response monitoring are required. One way to achieve this is by using molecular imaging, which can be used to measure the expression and accessibility of tumor-associated antigens in vivo, without the need of invasive biopsies. This review will focus on tumor-receptor imaging for currently approved targeted therapies and discuss the potential role of molecular imaging in the development of new therapeutic agents in breast cancer. Progress has been made in radionuclide imaging of ER, PR, HER2 and epidermal growth factor receptor (EGFR) expression, which can be used for treatment selection and response prediction to endocrine and other targeted therapy. Moreover, clinical studies have shown the feasibility for molecular imaging of the angiogenic pathway exploiting the expression of antigens closely associated with angiogenesis, such as αvß3 and VEGF. As proof of concept has been established, further research should be directed towards validation of the imaging methods and the impact on patient management.

Better survival in patients with metastasised kidney cancer after nephrectomy: a population-based study in the Netherlands.

AIM: Cytoreductive nephrectomy is considered beneficial in patients with metastasised kidney cancer but only a minority of these patients undergo cytoreductive surgery. Factors associated with nephrectomy and the independent effect of nephrectomy on survival were evaluated in this study. METHODS: Patients were selected from the population-based cancer registry and detailed data were retrieved from clinical files. Factors associated with nephrectomy were evaluated by logistic regression analyses. Cox proportional hazard regression analysis was performed to evaluate factors associated with survival; a propensity score reflecting the probability of being treated surgically was included in order to adjust for confounding by indication. RESULTS: 37.5% of 328 patients diagnosed with metastatic kidney cancer between 1999 and 2005 underwent nephrectomy. Patients with a low performance score, high age, ≥2 comorbid conditions, ≥2 metastases, low or high BMI, weight loss, elevated lactate dehydrogenase, elevated alkaline phosphatase, female gender and liver or bone metastases were less likely to be treated surgically. Three year survival was 25% and 4% for patients with and without nephrectomy, respectively (p<0.001). After adjustment for other prognostic factors including the propensity score, nephrectomy remained significantly associated with better survival (Hazard ratio: 0.52, 95% Confidence interval: 0.37-0.73). CONCLUSIONS: Even after accounting for prognostic profile, patients still benefit from a nephrectomy; an approximately 50% reduction in mortality was observed. It is, therefore, recommended that patients with metastasised disease receive cytoreductive surgery when there is no contraindication. Trial results on cytoreductive surgery combined with targeted molecular therapeutics are awaited for.