Topical GZ21T inhibits the growth of actinic keratoses in a UVB induced model of skin carcinogenesis

Bordeaux, Z. A.; Choi, J.; Braun, G.; Davis, C.; Marani, M.; Lee, K.; Samuel, C.; Adams, J.; Windom, R.; Kambala, A.; Cornman, H.; Reddy, S. V.; Pollizzi, A.; LU, W.; Oladipo, O. O.; Alphonse, M. P.; West, C. E.; Kwatra, S. G.; Kwatra, M. M.

doi:10.1101/2022.09.07.506864

bioRxiv · 10.1101/2022.09.07.506864

Topical GZ21T inhibits the growth of actinic keratoses in a UVB induced model of skin carcinogenesis

Bordeaux, Z. A.·Choi, J.·Braun, G.·Davis, C.·Marani, M.·Lee, K.·Samuel, C.·Adams, J.·Windom, R.·Kambala, A.·Cornman, H.·Reddy, S. V.·Pollizzi, A.·LU, W.·Oladipo, O. O.·Alphonse, M. P.·West, C. E.·Kwatra, S. G.·Kwatra, M. M.

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Abstract

Actinic keratoses (AKs) are premalignant intraepidermal neoplasms that occur as a result of cumulative sun damage. AKs commonly relapse, and up to 16% undergo malignant transformation into cutaneous squamous cell carcinoma (cSCC). There is a need for novel therapies that reduce the quantity and surface area of AKs as well as prevent malignant transformation to cSCCs. We recently showed that GZ17-6.02, an anti-cancer agent composed of curcumin, haramine, and isovanillin, inhibited the growth of H297.T cells. The present study evaluated the efficacy of a novel topical formulation of GZ17-6.02, known as GZ21T, in a murine model of AK generated by exposing SKH1 mice to ultraviolet irradiation. Treatment of mice with topical GZ21T inhibited the growth of AKs by decreasing both lesion count (p=.028) and surface area occupied by tumor (p=.026). GZ21T also suppressed the progression of AKs to cSCC by decreasing the count (p=.047) and surface area (p=.049) of lesions more likely to represent cSCC. RNA sequencing and proteomic analyses revealed that GZ21T suppressed several pathways, including MAPK (p=.026), Pi3K-Akt (p=.028), HIF-1 (p=.030), Wnt (p=.031), insulin (p=.011), and ErbB (p=.006) signaling. GZ21T also upregulated the autophagy-promoting protein AMPK, while suppressing proteins such as PD-L1, glutaminase, pAkt1 S473, and eEF2K. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/506864v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1254e6corg.highwire.dtl.DTLVardef@3fd190org.highwire.dtl.DTLVardef@1d75eb5org.highwire.dtl.DTLVardef@8afc97_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Bordeaux, Z. A., Choi, J., Braun, G., Davis, C., Marani, M., Lee, K., Samuel, C., Adams, J., Windom, R., Kambala, A., Cornman, H., Reddy, S. V., Pollizzi, A., LU, W., Oladipo, O. O., Alphonse, M. P., West, C. E., Kwatra, S. G., Kwatra, M. M.. 2022-09-07. Topical GZ21T inhibits the growth of actinic keratoses in a UVB induced model of skin carcinogenesis. https://doi.org/10.1101/2022.09.07.506864

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