scholarly journals Targeted Alpha Therapy Trial in Bangladesh: Promise for Advanced MUC1 – Expressing Tumors

2018 ◽  
Vol 19 (1) ◽  
pp. 43-50
Author(s):  
Lutfun Nisa ◽  
Kamila Afroj Quadir ◽  
Shamim MF Begum ◽  
Raihan Hussain ◽  
Mizanul Hasan
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Cancer Cells ◽  
Advanced Technology ◽  
Current Status ◽  
Targeted Alpha Therapy ◽  
Cancer Management ◽  
Tolerance Dose ◽  
Maximum Tolerance ◽  
Alpha Therapy

Introduction: Targeted alpha therapy (TAT) is a new experimental therapy that targets cancer cells and tumor capillary endothelial cells through intravenous injection of an alpha immuneconjugate (AIC). The AIC is formed by labeling the cancer targeting vector (monoclonal antibody) with alpha emitting radioisotopes using a bifunctionalchelator. The monoclonal antibody (MAb) is raised against antigens (e.g. MUC1) over-expressed on the surface of certain cancer cells. There are several centers notably in Europe, the US and Australia that are actively involved in TAT clinical trials of different cancers using a variety of techniques, alpha emitters and MAbs. Observations from their cumulative experience suggest that TAT is safe and effectivebut needs further trials for practical acceptance. Especially critical is the issue of maximum tolerance dose (MTD) which needs to be established for maximum target kill. Bangladesh has the infrastructure to conduct aTAT clinical trial and can significantly add to the growing pool of data for advanced treatment of cancers through collaborative involvement in targeted alpha therapy research.Objective: The aim of the article is to present a general overview of targeted alpha therapy and to discuss the feasibility of a TAT clinical trial in Bangladesh in the context of current cancer management situation in the country.Method: Literature review of significant publications was done to obtain an update of the current status of targeted alpha therapy. Relevant issues of TAT are presented for a theoretical basis of the technology. Next, the methodology of a proposed clinical trial is discussed, together with the practicability of its introduction in Bangladesh.Conclusion: Implementation of TAT clinical trial will help to develop an advanced technology and build- up skilled manpower in Bangladesh.It will optimize the key parameters of targeted alpha therapy, i e stability and specific activity of the alpha-conjugate and establish the maximum tolerance dose for the AIC. If the clinical trial is successful, it can change the prognosis of many end-stage cancers. Patients in Bangladesh with advanced MUCI expressing tumors of the breast, ovary, pancreas and prostate can have some measure of hope with stability of the disease.Bangladesh J. Nuclear Med. 19(1): 43-50, January 2016

scholarly journals Extended single-dose toxicity study of [211At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer

2021 ◽  
Author(s):  
Tadashi Watabe ◽  
Kazuko Kaneda-Nakashima ◽  
Kazuhiro Ooe ◽  
Yuwei Liu ◽  
Kenta Kurimoto ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Thyroid Cancer ◽  
Single Dose ◽  
General Condition ◽  
Blood Test ◽  
Differentiated Thyroid Cancer ◽  
Targeted Alpha Therapy ◽  
Evaluation Point ◽  
Alpha Therapy

Abstract Objective Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose. Methods [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups. Results No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt. Conclusions In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.

scholarly journals The Mode-of-Action of Targeted Alpha Therapy Radium-223 as an Enabler for Novel Combinations to Treat Patients with Bone Metastasis

2019 ◽  
Vol 20 (16) ◽  
pp. 3899 ◽  
Author(s):  
Mari I. Suominen ◽  
Timothy Wilson ◽  
Sanna-Maria Käkönen ◽  
Arne Scholz
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Cancer Cells ◽  
Bone Cells ◽  
Metastatic Cancer ◽  
Signal Molecules ◽  
Targeted Alpha Therapy ◽  
Radium 223 ◽  
Alpha Therapy

Bone metastasis is a common clinical complication in several cancer types, and it causes a severe reduction in quality of life as well as lowering survival time. Bone metastases proceed through a vicious self-reinforcing cycle that can be osteolytic or osteoblastic in nature. The vicious cycle is characterized by cancer cells residing in bone releasing signal molecules that promote the differentiation of osteoclasts and osteoblasts either directly or indirectly. The increased activity of osteoclasts and osteoblasts then increases bone turnover, which releases growth factors that benefit metastatic cancer cells. In order to improve the prognosis of patients with bone metastases this cycle must be broken. Radium-223 dichloride (radium-223), the first targeted alpha therapy (TAT) approved, is an osteomimetic radionuclide that is incorporated into bone metastases where its high-linear energy transfer alpha radiation disrupts both the activity of bone cells and cancer cells. Therefore, radium-223 treatment has been shown preclinically to directly affect cancer cells in both osteolytic breast cancer and osteoblastic prostate cancer bone metastases as well as to inhibit the differentiation of osteoblasts and osteoclasts. Clinical studies have demonstrated an increase in survival in patients with metastatic castration-resistant prostate cancer. Due to the effectiveness and low toxicity of radium-223, several novel combination treatment strategies are currently eliciting considerable research interest.

scholarly journals Systemic Targeted Alpha Radiotherapy for Cancer - A Review

2014 ◽  
Vol 6 (1) ◽  
pp. 21-38 ◽  
Author(s):  
Barry J Allen
Keyword(s):  
Glioblastoma Multiforme ◽  
Cancer Cells ◽  
Medical Physics ◽  
Metastatic Cancer ◽  
External Beam Radiotherapy ◽  
Palliative Therapy ◽  
Experimental Therapy ◽  
Alpha Radiation ◽  
Targeted Alpha Therapy ◽  
Alpha Therapy

The fundamental principles of internal targeted alpha therapy for cancer were established many decades ago. The high linear energy transfer (LET) of alpha radiation to the targeted cancer cells causes double strand breaks in DNA. At the same time, the short range of alpha- radiation spares adjacent normal tissues. This targeted approach complements conventional external beam radiotherapy and chemotherapy. Such therapies fail on several fronts, such as lack of control of some primary cancers (eg glioblastoma multiforme) and inhibition of the development of lethal metastatic cancer after successful treatment of the primary cancer. This review charts the developing role of systemic high LET in internal radiation therapy. Targeted alpha therapy is a rapidly advancing experimental therapy that holds promise to deliver high cytotoxicity to targeted cancer cells. Initially thought to be indicated for leukaemia and micrometastases, there is now evidence that solid tumours can also be regressed. Alpha therapy may be molecular or physiological in its targeting. Alpha emitting radioisotopes such as Bi-212, Bi-213, At-211 and Ac-225 are used to label monoclonal antibodies or proteins that target specific cancer cells. Alternatively, radium-233 is used for palliative therapy of breast and prostate cancers because of its bone seeking properties. In this review, preclinical studies and clinical trials of alpha therapy are discussed for leukaemia, lymphoma, melanoma, glioblastoma multiforme, bone metastases, ovarian cancer, pancreatic cancer and other cancers.   DOI: http://dx.doi.org/10.3329/bjmp.v6i1.19755 Bangladesh Journal of Medical Physics Vol.6 No.1 2013 21-38

scholarly journals Microdosimetry for Targeted Alpha Therapy of Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Chen-Yu Huang ◽  
Susanna Guatelli ◽  
Bradley M. Oborn ◽  
Barry J. Allen
Keyword(s):  
Cancer Cells ◽  
Antigen Expression ◽  
Hematologic Malignancies ◽  
Detailed Knowledge ◽  
Cell Geometry ◽  
Targeted Alpha Therapy ◽  
Normal Tissues ◽  
High Let ◽  
Therapeutic Doses ◽  
Alpha Therapy

Targeted alpha therapy (TAT) has the advantage of delivering therapeutic doses to individual cancer cells while reducing the dose to normal tissues. TAT applications relate to hematologic malignancies and now extend to solid tumors. Results from several clinical trials have shown efficacy with limited toxicity. However, the dosimetry for the labeled alpha particle is challenging because of the heterogeneous antigen expression among cancer cells and the nature of short-range, high-LET alpha radiation. This paper demonstrates that it is inappropriate to investigate the therapeutic efficacy of TAT by macrodosimetry. The objective of this work is to review the microdosimetry of TAT as a function of the cell geometry, source-target configuration, cell sensitivity, and biological factors. A detailed knowledge of each of these parameters is required for accurate microdosimetric calculations.

scholarly journals Towards Targeted Alpha Therapy with Actinium-225: Chelators for Mild Condition Radiolabeling and Targeting PSMA—A Proof of Concept Study

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1974
Author(s):  
Falco Reissig ◽  
David Bauer ◽  
Kristof Zarschler ◽  
Zbynek Novy ◽  
Katerina Bendova ◽  
...  
Keyword(s):  
Cell Survival ◽  
Mild Condition ◽  
High Efficiency ◽  
Whole Body ◽  
Binding Studies ◽  
Targeted Alpha Therapy ◽  
Cancer Management ◽  
Biodistribution Studies ◽  
Alpha Emitter ◽  
Alpha Therapy

Currently, targeted alpha therapy is one of the most investigated topics in radiopharmaceutical cancer management. Especially, the alpha emitter 225Ac has excellent nuclear properties and is gaining increasing popularity for the treatment of various tumor entities. We herein report on the synthesis of two universal 225Ac-chelators for mild condition radiolabeling and binding to conjugate molecules of pharmacological interest via the copper-mediated click chemistry. A convenient radiolabeling procedure was investigated as well as the complex stability proved for both chelators and two PSMA (prostate-specific membrane antigen)-targeting model radioconjugates. Studies regarding affinity and cell survival were performed on LNCaP cells followed by biodistribution studies, which were performed using LNCaP tumor-bearing mice. High efficiency radiolabeling for all conjugates was demonstrated. Cell binding studies revealed a fourfold lower cell affinity for the PSMA radioconjugate with one targeting motif compared to the radioconjugate owing two targeting motifs. Additionally, these differences were verified by in vitro cell survival evaluation and biodistribution studies, both showing a higher cell killing efficiency for the same dose, a higher tumor uptake (15%ID/g) and a rapid whole body clearance after 24 h. The synthesized chelators will overcome obstacles of lacking stability and worse labeling needs regarding 225Ac complexation using the DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid) chelator. Moreover, the universal functionalization expands the coverage of these chelators in combination with any sensitive bio(macro)molecule, thus improving treatment of any addressable tumor target.

Potential Therapeutic Targets of Curcumin, Most Abundant Active Compound of Turmeric Spice: Role in the Management of Various Types of Cancer

2020 ◽  
Vol 15 ◽  
Author(s):  
Saleh A. Almatroodi ◽  
Mansoor Ali Syed ◽  
Arshad Husain Rahmani
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Active Compound ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Cell Signalling ◽  
Chemopreventive Agents ◽  
Signalling Molecules ◽  
Cancer Management ◽  
Induced Apoptosis

Background:: Curcumin, an active compound of turmeric spice is one of the most-studies natural compounds and have been widely recognized as chemopreventive agents. Several molecular mechanisms have been proven, curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as inhibition of carcinogenesis process. Objective:: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents. Methods:: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed central and Google scholar for the implication of curcumin in cancer management along with special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com and www.freshpatents.com. Result:: Recent studies based on cancer cells have proven that curcumin have potential effects against cancer cells, prevent the growth of cancer and act as cancer therapeutic agents. Besides, curcumin exerted anticancer effects through inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells. Conclusion:: Accumulating evidences suggest that curcumin has potentiality to inhibit cancer growth, induced apoptosis and modulate various cell signalling pathways molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy and safe dose in the management of various cancers.

The Engaged Role of Tumor Microenvironment in Cancer Metabolism: Focusing on Cancer-Associated Fibroblast and Exosome Mediators

2020 ◽  
Vol 21 (2) ◽  
pp. 254-266 ◽  
Author(s):  
Khandan Ilkhani ◽  
Milad Bastami ◽  
Soheila Delgir ◽  
Asma Safi ◽  
Shahrzad Talebian ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metabolism ◽  
Krebs Cycle ◽  
Metabolic Reprogramming ◽  
Cancer Management ◽  
Cancer Associated Fibroblast ◽  
Potential Biomarker ◽  
Close Relationship ◽  
Microenvironmental Factors

: Metabolic reprogramming is a significant property of various cancer cells, which most commonly arises from the Tumor Microenvironment (TME). The events of metabolic pathways include the Warburg effect, shifting in Krebs cycle metabolites, and the rate of oxidative phosphorylation, potentially providing energy and structural requirements for the development and invasiveness of cancer cells. TME and tumor metabolism shifting have a close relationship through bidirectional signaling pathways between stromal and tumor cells. Cancer- Associated Fibroblasts (CAFs), as the most dominant cells of TME, play a crucial role in the aberrant metabolism of cancer. Furthermore, the stated relationship can affect survival, progression, and metastasis in cancer development. Recently, exosomes are considered one of the most prominent factors in cellular communications considering effective content and bidirectional mediatory effect between tumor and stromal cells. In this regard, CAF-Derived Exosomes (CDE) exhibit an efficient obligation to induce metabolic reprogramming for promoting growth and metastasis of cancer cells. The understanding of cancer metabolism, including factors related to TME, could lead to the discovery of a potential biomarker for diagnostic and therapeutic approaches in cancer management. This review focuses on the association between metabolic reprogramming and engaged microenvironmental, factors such as CAFs, and the associated derived exosomes.

Nanoconstructs in Targeted Alpha-Therapy

2015 ◽  
Vol 4 (2) ◽  
pp. 71-76 ◽  
Author(s):  
Jan Kozempel ◽  
Martin Vlk
Keyword(s):  
Targeted Alpha Therapy ◽  
Alpha Therapy

scholarly journals Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 795
Author(s):  
Lukas Gorecki ◽  
Martin Andrs ◽  
Jan Korabecny
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Patient Survival ◽  
Current Status ◽  
Future Perspectives ◽  
Phase Ii Trials ◽  
Anticancer Treatment ◽  
Positive Outlook ◽  
Insight Into

Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra‑S or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intra‑S and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival.

scholarly journals Sympathetic activity in breast cancer and metastasis: partners in crime

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Francisco Conceição ◽  
Daniela M. Sousa ◽  
Joana Paredes ◽  
Meriem Lamghari
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Bone Remodeling ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Sympathetic Innervation ◽  
Breast Cancer Progression ◽  
Vicious Cycle ◽  
Native Bone ◽  
Cancer Management

AbstractThe vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of life. Breast cancer cells are characterized by a strong tropism to the bone niche. After engraftment and colonization of bone, breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic “metastatic vicious cycle”. The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis, potentiating and accelerating the onset of the vicious cycle and leading to extensive bone degradation. Furthermore, sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer, such as proliferation, angiogenesis, immune escape, and invasion of the extracellular matrix. In this review, we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment, with a special emphasis on sympathetic modulation of breast cancer cells and stromal cells. Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options. In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted. In particular, we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche. Finally, clinical perspectives and developments on the use of β-adrenergic receptor inhibitors for breast cancer management and treatment are discussed.

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