Leukemic cells are very sensitive
Leukemic gtpase are very sensitive to radiation induced apoptosis, but the magnitude of the TBI radiation dose is dictated not only by the need to control tumor cells, but also to respect normal tissue tolerances of critical organs. Dose dependent late-effects of TBI are of particular concern in the treatment of pediatric patients. In addition to acute pulmonary, cardiovascular, hepatic, and renal toxicities, treatment of children can result in endocrinopathies, neurocognitive impairment, growth disturbances, cataract formation and secondary malignancies as delayed effects (). Thus, pediatric clinical protocols focus on reducing or eliminating radiation; however, multiple clinical trials have shown that including TBI is more effective than chemotherapy alone, and even minor reductions of TBI dose have resulted in more relapses ().
Although leukemias are generally considered radiation sensitive diseases, the clinically acceptable TBI doses are within tolerance of critical structures and may be insufficient for patient cure. Uckun\'s characterization of B-cells from recurrent leukemic patients as “radiation resistant” may be viewed in the context of such surviving malignant cells following exposure to conventional doses of TBI (). The high-risk B-precursor acute lymphoblastic leukemia (BPL) patients experience a high rate of relapse after conventional therapies and may benefit from innovative personalized treatment strategies based on an understanding of molecular genetics and pathogenesis of leukemias ().
The development of a cancer specific radiosensitizer, to allow TBI dose reduction and to increase treatment effectiveness, is a highly desired goal for leukemia treatment. To this end, Uckun and colleagues report that CD19L-sTRAIL preferentially kills leukemic stem cells from B-cell precursor ALL patients and enhances the killing effects of low dose TBI (). Furthermore, survival benefit, safety and efficacy of the combination treatment are demonstrated in proof-of-concept experiments in a xenograft animal model. Thus, sensitization of B-precursor ALL by the combination of radiation and the CD19L-sTRAIL fusion protein has potential for improving efficacy of treatment and allowing reduction in the radiation dose used for TBI. Although the effectiveness of TRAIL targeted therapy has yet to be demonstrated in clinical trials, recombinant protein therapies show promise in solid tumor clinical applications for targeted cancer treatment. Uckun\'s proposal to include CD19L-sTRAIL in the pre-transplant TBI regimens for patients presenting with very high risk BPL is a rational and innovative translational goal.
Conflicts of Interest
Acquired resistance to molecularly targeted therapies is a major obstacle blocking effective treatment of cancer patients. This is particularly true for therapies that target the epidermal growth factor receptor (EGFR) . Acquired resistance to molecularly targeted therapies may occur (meaning as a consequence of the selective pressure of treatment), or may be due to outgrowth of preexisting tumor subpopulations that are resistant to treatment . Clinical studies have shown that undetected populations of tumor cells carrying mutations lead to therapeutic resistance and relapse in colorectal cancer (CRC) patients . Consequently, the ability to assess the impact of minor mutant subpopulations on therapeutic resistance has important implications regarding the development of effective strategies for personalized cancer treatment. Detecting and analyzing the major and minor mutant subpopulations of cells carrying specific oncogene mutations in a patient\'s tumor, therefore, are crucial. The presence of some mutations, especially codon 12 mutations, in CRC patients is associated with poor prognosis and predicts lack of response to therapies that target the EGFR (e.g.,cetuximab, and panitumumab) . Therefore, detecting mutations is important for CRC patients undergoing anti-EGFR therapy. Mutations in occur most frequently on exon 2 (codons 12 and 13) and to a lesser extent on exon 3 (codon 61). The multicenter RASCAL study provided evidence that there were different prognoses for CRC patients harboring different mutations in their tumors. codon 12 mutations, especially G12V, is associated with poor prognosis, whereas patients with codon 13 mutations respond better to the therapies . Accurate detection of mutations that occur at high and low frequency is critical for identifying the best strategies for intervention. An ideal assay for detection of mutations: 1) should have the ability to determine mutations with high levels of specificity and sensitivity, 2) be able to determine different levels of mutations in colorectal tumors quantitatively, 3) should also be able to detect minor mutant subpopulations of mutations; and 4) should employ a multiplex approach, in order to detect several mutations from small amount of DNA in a short turnaround time.