- Researchers from Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) have recently developed a theranostics (diagnostic therapy) drug candidate for lung cancer, which is reportedly the most common cause of cancer-related death worldwide and is tough to detect at early stages.
- The selective recognition and imaging of oncogene specific non-canonical DNA secondary structures (G-quadruplex-GQ structures) holds great promise in the development of diagnostic therapy (theranostics) for cancer and has been challenging due to their structural dynamics and diversity.
- They developed a small molecule for selective recognition of BCL-2 GQ through unique hybrid loop stacking and groove binding mode with turn on far-red fluorescence response and anticancer activity demonstrating the potential as GQ-targeted lung cancer theranostics.
- Team reported the theranostic activity of TGP18 molecule by turn on fluorescence recognition of BCL-2 GQ through unique hybrid binding mode as well as its anti-lung cancer activity and tissue imaging potential.
- Their strategy of specific topology recognition through hybrid binding mode led to capitalize on the gains of oxidative stress and genome instability to kill lung cancer cells in vivo.
- In addition, TGP18 with turn on emission band at the lower edge of far-red to NIR spectroscopic window proved to be a viable probe for tumour tissue imaging.
- Collectively, theranostic agent TGP18 with outstanding biocompatibility showed in vivo tumor inhibition and tissue imaging, indicating excellent clinical translational potential.
- G-quadruplexes (GQs) are non-canonical DNA secondary structures which regulate a wide range of cellular processes, including expression of several oncogenes.
- In cancer cells, stabilization of GQs leads to replication stress and DNA damage accumulation and therefore considered as promising chemotherapeutic target.
- Despite the significant attempts to combine therapeutic and diagnostic properties in a single formulation, there are no concerted reports on small molecule theranostics.
- Similarly, there are no molecules reported for the topology selective recognition of myriad of GQs, especially oncogenic GQs.
- This study by the JNCASR team revealed that the selective recognition originating from the distinct loop structure of GQ that alters the overall probe interaction and binding affinity.
- TGP18 binding to anti-apoptotic BCL-2 GQ ablates the pro-survival function and elicit anti-cancer activity by inducing death in cancer cells.
- The JNCASR team deciphered that inhibition of BCL-2 transcription synergized with signalling cascade of nucleolar stress, DNA damage, and oxidative stress in triggering apoptosis signalling pathway.
- The intervention of GQ mediated lethality by TGP18 translated into anti-cancer activity in both in vitro 3D spheroid culture and in vivo xenograft models of lung and breast cancer with superior efficacy for the former.
- In vivo therapeutic efficacy, supplemented with tumor 3D spheroid and tissue imaging potential define the role of TGP18 in GQ-targeted cancer theranostics.
- According to their findings, a remarkably lower dosage of TGP18 (0.5 mg/kg) showed anti-lung tumor activity similar to anticancer drug gemcitabine at a very high dose of 100 mg/kg.
- The therapeutic agent TGP18 was found to reach the target tumor site as monitored by its far-red imaging of the tumor tissue.
