Long Term Direct Targeting and in Vivo Suppression of Tumor-Promoting Genes and Oncogenes

Our group has taken a novel approach for treating malignant tumors. It is based upon the understanding that genes in cancer cells are frequently mutated and overexpressed. These include proto-oncogenes, such as c-myc and kRAS, and the hTERT gene, all of which promote tumor growth and are identified during the molecular profiling of tumor biopsies. Their actions are associated with the immortalization of the cancer cell when their protein products activate the telomerase enzyme and lengthen the telomeric ends of DNA. The TMPyP4 porphyrin was shown, by numerous investigators, to suppress c-myc transcription, and inhibit hTERT, a catalytic subunit of telomerase. TMPyP4 binds to G-quadruplexes (GQ), guanine-rich sequences in the promoter region of DNA and prevents transcription. Specific targeting of these genes in an in vivo situation is severely restricted by the systemic administration of anticancer drugs that injure normal cells. We overcame the problem by developing a Poly-Lacto co-Glycolic Acid (PLGA) drug delivery system, in the form of a sustained release solid rod, which is implanted directly into the tumor. The PLGA is homogenously incorporated with TMPyP4, tagged with a palladium atom (PdTMPyP4). PdTMPyP4 is released into the tumor during the ~30 day degradation of the 3mm x 1.5mm PLGA polymeric rod. Long term, intratumoral, sustained release, is a critical aspect of in vivo gene targeting because the exact time when the DNA transcribes its genes is unknown and unpredictable. The drug must be continuously available to bind to GQ DNA in cancer cells to capture the moment when transcription begins. Additionally, when bound to GQ DNA, Pd enhances the tumor dose from iodine-125 (¹²⁵I) brachytherapy radiation. The photon energies from ¹²⁵I induce a photoelectric effect in the Pd atom and the emission of short range, low energy Auger electrons. These densely ionize the DNA and offer a therapeutic gain factor of >2 to the brachytherapy procedure. Thus, the sustained release of PdTMPyP4 from the intratumorally implanted PLGA can be used alone to target tumor-promoting genes, inhibit telomerase and reduce the tumor growth rate. Or, together with ¹²⁵I brachytherapy seeds implanted simultaneously in the tumor with the rod, can offer the potential of a curative treatment. We have shown a 5-fold reduction in the tumor growth rate of an aggressive murine mammary carcinoma in 4 independent studies comprising ~100 mice. 45 tumors with the rod implanted grew 5 times slower than 48, without the rod. Kaplan-Meier log rank statistics yielded a p-value of 0.0001 for the experiments. Spectrophotometry studies showed that PdTMPyP4 negligibly entered the blood serum after its implantation into tumor. Therefore, our proposed treatment will mitigate the adverse effects of different cancer treatments and will not affect the quality of life of the patient.