Gene, Light Therapy Combo Shows Promise Against Prostate Cancer Cells in Proof-of-Concept Study

Combining gene therapy with light therapy, researchers say they have found a potential new approach to treating prostate cancer, publishing their proof-of-concept findings in Molecular Therapy: Oncology.

Scientist analyzing gene transfer | Image Credit: © Bojan - stock.adobe.com

In their preclinical model, the researchers found efficacy both in vitro and in vivo by using CRISPR-Cas9 to mimic porphyria and combining the technology with light therapy. Their approach, according to the researchers, can serve as an alternative to photodynamic therapy.

Interest in using CRISPR-Cas9 across various disease states continues to grow, including in oncology. To date, CRISPR-Cas9 in this setting has demonstrated an ability to boost antitumor activity in chimeric antigen receptor T cells ex vivo by inactivating PD1 or TCR.

“Another way to use CRISPR-Cas9 in cancer gene therapy could be to inactivate a key gene directly in a tumor. However, this promising approach is still underdeveloped,” the researchers explained. “In this context, canonical metabolic pathways are promising because they are highly conserved, even within a tumor, and are not dependent on tumor genomic heterogeneity/instability. Mimicking genetic metabolic disorders in cancer cells could be an alternative way to weaken them. Using expertise gained previously, we propose to mimic porphyria by targeting the heme biosynthesis pathway, which is essential to the proper functioning of cells and without any possible escape.”

The researchers chose to test their CRISPR-based approach in prostate cancer because of the location, which allows direct injection of gene therapy and the application of light therapy.

Using prostate cancer cells, the group first inactivated UROS in vitro in order to initiate photoreactive red fluorescent type 1 porphyrin accumulation. Using a lentiviral vector with the CRISPR-Cas9 nuclease sequence, the group found that the inactivation of UROS sensitized the cells to 405-nm light. The researchers found similar findings in vivo in mice, although they observed extensive dermatoxicity with skin burns and damage at the areas targeted by the light. Using longer light wavelengths mitigated the dermatoxicity, leading the researchers to move forward with 530-nm light exposure.

The researchers then tested the combination of the light therapy with the UROS gene therapy by subcutaneously injecting mice with either wild-type or UROS KO PC3 cells and applying repeat light exposure treatment. After 1 week of light therapy, the researchers observed significant reductions in tumor bioluminescence imaging signal intensity and tumor volume. Between days 7 and 10, tumors were undetectable. The combination therapy at 1 week was associated with 2-fold improved survival among the mice (34 days vs 17 days). No dermatoxicity was observed.

Despite the initial success, the researchers noted slight relapse at approximately day 17, following 3 light therapy sessions, leading the group to assess the efficacy of a 5-week illumination protocol. The researchers again found promising efficacy in the first 2 weeks, which was followed by a secondary tumor relapse at week 3. Investigating further, the researchers found large peripheral reactional fibrosis, suggesting that their illumination approach didn’t reach tumor cells.

“Although these results obtained with an external light-emitting diode (LED) are promising, a therapeutic escape occurred. This may have been caused by a reduction in illumination penetrance due to the remodeling of tumoral and peritumoral tissues,” detailed the researchers. “Thanks to the advent of interstitial lasers, it is now possible with endoscopic optical fibers to illuminate the interior of tumors, in direct contact with cancer cells. Therefore, interstitial illumination combined with UROS gene therapy may lead to a longer response to treatment and could overcome the relapse. Moreover, human cancer cell xenografts require immunodeficient mice. We hypothesize that immunocompetent models obtained by using syngeneic mouse prostate tumors should allow the recruitment of the immune system, thus reinforcing the efficacy of our approach.”

Reference

Boutin J, Genevois C, Coillaud F, et al. CRISPR editing to mimic porphyria combined with light: a new preclinical approach for prostate cancer. Mol Ther Oncol. 2024;32(1):200772. doi:10.1016/j.omton.2024.200772