Conventional anticancer treatments such as cytotoxic chemotherapy and radiotherapy are limited by serious side effects arising from their intrinsic toxicities, and are generally far from curative 1
. Though recent advances have been achieved with targeted molecular anticancer therapies, inherent hurdles for cancer cure through nonexclusive mechanisms cannot be ignored. For instance, target mutation and escape, target amplification, and down/upregulation of mechanisms may lower the intracellular drug concentration and/or activation of complementary pathways 2,3
. On the other hand, cancer stem cells (CSCs) are located in the specific microenvironment and are generally resistant to chemotherapies; these surviving CSCs then repopulate the tumor, causing relapse. Thus, hitting the evasive targets in cancer still proves a major challenge 4,5
. Clinically, tumor residue after therapies presents always a culprit for cancer recurrence and patient death.
In developing highly efficient targeting cancer therapies, there are two additional opportunities. First, homeostatic factors that compose up to 90% of the tumor mass in some tumors have great essentiality to influence the level of malignant aggression and treatment outcomes 6
. Homeostatic factors render tumor microenvironment also as a therapeutic target besides cancer cells 7
. Secondly, necrotic tissues, which comprise 30-80% of a solid tumor and locate always close to the viable cancer cells, can function as a universal anchor for targeting malignancies 8-11
. Therapeutic use of iodine-131 in patients with thyroid cancer has been proven highly effective with ablation rate over 80% 12,13
. In order to translate such a success to broader indications or even a generalized strategy for solid tumors, efforts have been made to render tumor affinity and sensitivity to iodine-131, i.e., allowing iodine-131 to highly concentrate inside viable tumor cells or close to them within the beta-irradiation range. That way, improved treatability or even curability can be expected for patients with different kinds of solid tumors. Furthermore, various other therapies of synergistic or complementary antitumor effects with different mechanisms can be combined for more thorough elimination of cancer cells.
Recently, a general and unconventional anticancer approach namely small molecule sequential dual targeting theragnostic strategy (SMSDTTS) has been introduced 11
. SMSDTTS aims to target and debulk the tumor mass, wipe out the residual tumor cells, and meanwhile enable cancer detectability. SMSDTTS works in two-steps for systemic delivery of two naturally derived drugs. First, an anti-tubulin vascular disrupting agent (VDA) such as combretastatin A4 phosphate (CA4P) is injected to selectively cut off tumor blood supply and to cause massive necrosis, which though always leaves peripheral residues. Secondly, a necrosis-avid radiopharmaceutical such as 131
I-Hyp) is administered the next day, which accumulates in intratumoral necrosis and irradiates the neighboring cancer cells with beta particles to prevent tumor relapse. Theoretically, this complementary targeting approach may biologically and radioactively ablate solid tumors and reduce the risk of local recurrence, remote metastases, and thus cancer mortality. Meanwhile, the gamma rays emitted by iodine-131 enable radio-scintigraphy to detect the tumors and follow up the therapy, hence constituting a simultaneous theragnostic approach (Fig. ). Based on the above-mentioned unique rationales, SMSDTTS may precisely hit two stable targets within the stroma domain by selectively destroying the tumoral vessels and sterilizing tumor microenvironment. Thus, the SMSDTTS seems advantageous over other existing therapies and deserves further preclinical and clinical development 11
Figure 1 Schema illustrates the mechanisms of the small molecule sequential dual-targeting anticancer strategy (SMSDTTS): first to treat the solid tumor and to cause massive tumor necrosis by using CA4P. After being iv injected 24h later, 131I-Hyp accumulates (more ...)
Exploiting the true natural power, this new strategy has now shown promise in multicenter animal experiments, and may demonstrate superior anticancer efficacy and clinical safety in upcoming preliminary clinical trials. In this short review article, information about the two involved agents, the hypotheses/rationales, preclinical antitumor efficacy, multifocal targetability, and simultaneous theragnostic property of SMSDTTS in different animal tumor models, as well as toxicities of the dose regimens are summarized. Meanwhile, possible drawbacks, practical challenges and future improvement with SMSDTTS are also discussed, which hopefully may help to push forward this strategy from preclinical experiments towards possible clinical applications.