Molecular Pathways Molecular Pathways: Targeted a-Particle Radiation Therapy

An a-particle, a He nucleus, is exquisitely cytotoxic and indifferent to many limitations associated with conventional chemoand radiotherapy. The exquisite cytotoxicity ofa-radiation, the result of its highmean energy deposition [high linear energy transfer (LET)] and limited range in tissue, provides for a highly controlled therapeutic modality that can be targeted to selected malignant cells [targeted a-therapy (TAT)] with minimal normal tissue effects. A burgeoning interest in the development of TAT is buoyed by the increasing number of ongoing clinical trialsworldwide. The short path length rendersa-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking, hematologic cancers, infections, and compartmental cancers such as ovarian cancer or neoplastic meningitis. Yet, despite decades of study of high LET radiation, the mechanistic pathways of the effects of this modality remain not well defined. The modality is effectively presumed to follow a simple therapeutic mechanism centered on catastrophic double-strand DNA breaks without full examination of the actual molecular pathways and targets that are activated that directly affect cell survival or death. This Molecular Pathways article provides an overview of themechanisms and pathways that are involved in the response to and repair of TAT-induced DNA damage as currently understood. Finally, this article highlights the current state of clinical translation of TAT as well as other high-LET radionuclide radiation therapy using a-emitters such as Ac, At, Bi, Pb, and Ra. Clin Cancer Res; 19(3); 530–7. 2012 AACR. Background An a-particle is a naked He nucleus; therefore, it is relatively heavier than other subatomic particles emitted from decaying radionuclides and nuclear reactions such as electrons, neutrons, and protons. With a þ2 charge, a-particles aremore effective ionization agents, have a high linear energy transfer (LET), in the range of 100 KEV/mm, and are highly efficient in depositing energy over a short range in tissue (50–100 mm). An a-particle deposits 500 times more energy per unit path length than an electron or b -particle. Unlike low-LET radiation (conventional x-, g-, and electron-like radiation), the cytocidal efficacy of a-particle radiation is indifferent to dose fractionation, dose rate, or hypoxia and also overcomes the resistance to chemotherapeutics encountered in conventional chemoand radiotherapy. The a-emitting radionuclides that are medically relevant and available for potential clinical use at this time are At, Bi, Bi, Ac, Ra, Pb, Th, and Tb. The use of a-particle radiation as a therapeutic modality was recognized almost concurrently with the discovery of particle radiation by Rutherford in 1898 from which evolved the use of radium radionuclide brachytherapy applications (1). Although there are several isotopes of radium, Ra (Alpharadin) has recently moved to the forefront for clinical translation to treat bone metastases (vide infra; ref. 2), whereas Ra has had application in the treatment of bone diseases such as ankylosing spondylitis (3). However, the targeting of radium radionuclide relies solely upon the physicochemical nature of this element, which dictates the innate unaided biodistribution properties of the radium ion and as such does not qualify as a targeted a-therapy (TAT). For TAT, a molecular target is chosen and the a-emission delivered to that chosen location and site. In fact, at this time, the necessary chemistry to conduct TAT with radium is not yet available (4). A highly desirable goal in cancer therapy that has eluded clinicians is the ability to target malignant cells while sparing normal cells. If significant differential targeting is achieved by the vector, then a toxic payload on the vector will deliver a lethal dose preferentially to those cells expressing higher concentrations of the target molecule, thereby sparing nearby normal cells. TAT seeks to achieve this goal by using highly cytotoxic a-particle radiation carried to specific sites of cancer by appropriate vectors. The short path length of the a-particle addresses the concern of sparing normal tissue by limiting energy delivery, upon which cell killing depends within the cell where it is delivered, and as indicated above, reverses resistance to chemotherapy or conventional radiotherapy. The short path length also renders a-emitters suitable for treatment and Authors' Affiliation: Radioimmune & Inorganic Chemistry Section, ROB, National Cancer Institute, NIH, Bethesda, Maryland Corresponding Author: Martin W. Brechbiel, Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, NCI, NIH, 10 Center Drive, Building 10, Rm B3B69, Bethesda, MD 20892. Phone: 301-496-0591; Fax 301-402-1923; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-12-0298 2012 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 19(3) February 1, 2013 530 on July 15, 2017. © 2013 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst December 10, 2012; DOI: 10.1158/1078-0432.CCR-12-0298