Bone-targeted Novel Cytotoxic Polybisphosphonate Conjugate in Castration-resistant Prostate Cancer: A Multicenter Phase 1 Study

Thellenberg‐Karlsson, Camilla; Nyman, Claes R.; Nilsson, Sten; Blom, René; Márquez, Marcela; Castellanos, Enrique; Holmberg, Anders

doi:10.21873/anticanres.11249

Cited by 13 publications

(9 citation statements)

References 20 publications

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“…In vitro studies demonstrated that ODX had similar potency to inhibit bone resorption as zoledronate, but it also killed PC3 cells, a cell line established in 1979 from a bone metastasis of a 62-year-old Caucasian male with grade IV prostate cancer, with 10-fold higher potency than zoledronate (IC50 2 μm vs. 25 μm) [53]. DexTech completed a Phase 1 open-label, multiple ascending dose, multicenter clinical trial of ODX (ClinicalTrials.gov NCT02825628) and reported the results in 2016 [54]. Twenty-eight patients with castration-resistant prostate cancer and confirmed bone metastases were given 7 intravenous infusions of ODX every third week.…”

Section: Osteodex (Odx)mentioning

confidence: 99%

Targeting anti-cancer agents to bone using bisphosphonates

Xing

Ebetino

Boeckman

et al. 2020

Bone

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The skeleton is affected by numerous primary and metastatic solid and hematopoietic malignant tumors, which can cause localized sites of osteolysis or osteosclerosis that can weaken bones and increase the risk of fractures in affected patients. Chemotherapeutic drugs can eliminate some tumors in bones or reduce their volume and skeletal-related events, but adverse effects on non-target organs can significantly limit the amount of drug that can be administered to patients. In these circumstances, it may be impossible to deliver therapeutic drug concentrations to tumor sites in bones. One attractive mechanism to approach this challenge is to conjugate drugs to bisphosphonates, which can target them to bone where they can be released at diseased sites. Multiple attempts have been made to do this since the 1990s with limited degrees of success. Here, we review the results of pre-clinical and clinical studies made to target FDA-approved drugs and other antineoplastic small molecules to bone to treat diseases affecting the skeleton, including osteoporosis, metastatic bone disease, multiple myeloma and osteosarcoma. Results to date are encouraging and indicate that drug efficacy can be increased and side effects reduced using these approaches. Despite these successes, challenges remain: no drugs have gone beyond small phase 2 clinical trials, and major pharmaceutical companies have shown little interest in the approach to repurpose any of their drugs or to embrace the technology. Nevertheless, interest shown by smaller biotechnology companies in the technology suggests that bone targeting of drugs with bisphosphonates has a viable future.

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Section: Osteodex (Odx)mentioning

confidence: 99%

Targeting anti-cancer agents to bone using bisphosphonates

Xing

Ebetino

Boeckman

et al. 2020

Bone

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“…OsteoDex is a bi-functional macromolecular polybisphosphonate has osteoclast inhibitory function with anti-tumor ability [107,108]. A phase I safety study were performed in castration-resistant prostate cancer patients revealed no serious adverse effects, including renal toxicity [107]. Currently, a phase II trial testing the effect of osteodex on skeletal related pain in prostate cancer patients with bone metastases is underway (ClinicalTrias.gov: NCT02825628).…”

Section: Treatment Strategies For Men With Bone Metastasesmentioning

confidence: 99%

“…Additionally, another potential bone-targeting reagent, OsteoDex has been recently developed. OsteoDex is a bi-functional macromolecular polybisphosphonate has osteoclast inhibitory function with anti-tumor ability [107,108]. A phase I safety study were performed in castration-resistant prostate cancer patients revealed no serious adverse effects, including renal toxicity [107].…”

Section: Treatment Strategies For Men With Bone Metastasesmentioning

confidence: 99%

Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis

2017

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Bone is the most common site of prostate cancer metastasis. Once prostate cancer cells metastasize to bone, the mortality rate of prostate cancer patients increases significantly. Furthermore, bone metastases produce multiple skeletal complications, including bone pain that impairs the patients' quality of life. Effective therapies for bone metastatic disease are underdeveloped with most current therapies being primarily palliative with modest survival benefit. Although the exact mechanisms through which prostate cancer metastasizes to bone are unclear, growing evidence suggests that the bone marrow microenvironment, particularly its hematopoietic activity, is a significant mediator of prostate cancer bone tropism. Moreover, the bone microenvironment may regulate metastatic prostate cancer cells between dormant and proliferative states. In this review, we discuss (1) how prostate cancer cells interact with the bone microenvironment to establish bone metastases and (2) current and future potential treatments for prostate cancer patients with bone metastases.

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“…4) Although docetaxel provides a modest (2.4-month) increase in median overall survival, many patients with CRPC cannot tolerate this cytotoxic chemotherapy due to advanced age, medical comorbidities, or limited bone marrow reserves. 5) Therefore, the identification of an effective alternative therapy with less toxicity may lead to increased survival and an improved QOL.…”

mentioning

confidence: 99%

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

Wang

Huang

Zhang

et al. 2017

Biological & Pharmaceutical Bulletin

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Metformin is a commonly used drug for the treatment of type II diabetes and atorvastatin is the most prescribed cholesterol-lowering statin. The present study investigated the effects and mechanisms of metformin and atorvastatin in combination on human prostate cancer cells cultured in vitro and grown as xenograft tumor in vivo. Metformin in combination with atorvastatin had stronger effects on growth inhibition and apoptosis in PC-3 cells than either drug alone. The combination also potently inhibited cell migration and the formation of tumorspheres. Metformin and atorvastatin in combination had a potent inhibitory effect on nuclear factor-kappaB (NF-κB) activity and caused strong decreases in the expression of its downstream anti-apoptotic gene Survivin. Moreover, strong decreases in the levels of phospho-Akt and phosphorextracellular signal-regulated kinase (Erk)1/2 were found in the cells treated with the combination. The in vivo study showed that treatment of severe combined immunodeficient (SCID) mice with metformin or atorvastatin alone resulted in moderate inhibition of tumor growth while the combination strongly inhibited the growth of the tumors. Results of the present study indicate the combination of metformin and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.Key words prostate cancer; atorvastatin; metformin; apoptosis; combination Prostate cancer is one of the common types of malignant disease in males in the world and is the second leading cause of cancer-related death in the United States. The American Cancer Society estimates for 2016 approximately 180890 new cases will be diagnosed and 26120 men will die of the disease, accounting for about 8.3% of male cancer-related deaths. 1)Androgen deprivation therapy is an effective treatment for advanced prostate cancer. Unfortunately, almost all patients treated with androgen deprivation therapy will progress to castration-resistant prostate cancer (CRPC).2,3) Docetaxel is the most commonly prescribed first-line chemotherapy for CRPC. 4) Although docetaxel provides a modest (2.4-month) increase in median overall survival, many patients with CRPC cannot tolerate this cytotoxic chemotherapy due to advanced age, medical comorbidities, or limited bone marrow reserves. 5)Therefore, the identification of an effective alternative therapy with less toxicity may lead to increased survival and an improved QOL.Metformin is a well-established agent for the treatment of type II diabetes. In addition to its efficacy in lowering glucose levels, recent reports indicate it may have antitumor effects in various cancers, including prostate cancer. 6) Diabetic patients receiving metformin have been shown to have a reduced cancer incidence and a decrease in cancer-specific mortality.7) Further, epidemiologic evidence revealed a decreased incidence of prostate cancer in men taking metformin, 8,9) and both animal and in vitro models demonstrate its activity in prostate cancer cell lines. 10,11) Finall...

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Bone-targeted Novel Cytotoxic Polybisphosphonate Conjugate in Castration-resistant Prostate Cancer: A Multicenter Phase 1 Study

Cited by 13 publications

References 20 publications

Targeting anti-cancer agents to bone using bisphosphonates

Targeting anti-cancer agents to bone using bisphosphonates

Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

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