Via Research Recognition Day Program VCOM-Carolinas 2025

Biomedical Research

THE ROLE OF PERSONALIZED MEDICINE IN CHEMOTHERAPY INVOLVING HISTONE DEACETYLASE INHIBITORS AND COMMON CHEMOTHERAPEUTIC DRUGS USED WITH THEM IN COMBINATION THERAPY. Annabel Crippen, OMS-III 1 , Steven Enkemann, PhD 2 . 1. VCOM Carolinas, Genetics, Spartanburg, SC. 2. Precision Genetics., Greenville, SC.

Results

Introduction

Discussion

Table 2 Enzymes involved in the metabolism of chemotherapeutic agents used in HDAC combination therapy. Each of the chemotherapeutic agents listed above have been investigated for the enzymes that metabolize them where human variation may impact activity. Table 1 The three main HDAC inhibitors and the traditional chemotherapeutic agents they have been combined with to treat cancer. HDAC Inhibitor Romidepsin Vorinostat Belinostat Each HDACi has been used in combination with each of the drugs (or combinations) listed below it. Combination 1 5-azacytidine Tamoxifen Doxorubicin Combination 2 Lenalidomide Carboplatin, Paclitaxel C d y o c x l o o r p u h b o ic s i p n h , a v m in i c d r e is , tine, and prednisone Combination 3 Pralatrexate HDAC inhibitors have been used in multiple combinations with other chemotherapeutic agents.

Combination therapy means many enzymes influence the efficacy and toxicity of a treatment.

Cancer therapy is a dynamic field that is ever evolving. Most drugs currently used to treat cancer target some aspect of rapidly dividing cells. This includes DNA replication pathways, topoisomerases and microtubules vital for replication, and DNA repair pathways. However, these therapies do not differentiate between cancer and normal cells that also replicate, leading to significant side effects. Emerging research suggests that genetic mutations in epigenetic pathways play a role in cancer development by altering regulatory gene expression (Dawson, 2006). This has led to the development of new drugs that target epigenetic pathways and their impact on oncogenesis. Important regulators include histone acetyltransferases (HAT) and histone deacetyltransferases (HDACs). These two molecules function on opposite sides of the balance between de-condensed and condensed chromatin influencing the genes expressed based on a cell's needs (Eckschlager, 2017). HDAC 1, 2 and 3 were found to be overexpressed in multiple different cancers indicating that they could be important therapeutic targets (Eckschlager, 2017). Thus, HDAC inhibitors (HDACis), such as Belinostat, Vorinostat, and Romidepsin have been developed to target HDACs and have shown some potential in reactivating silenced tumor suppressor genes through increased histone acetylation. Romidepsin and belinostat have been approved for the treatment of Peripheral T-Cell Lymphoma (PTCL), while vorinostat is approved for Cutaneous T-Cell Lymphoma (CTCL). However, HDAC inhibitors have shown limited success rates when used as a monotherapy in solid tumors and resistance to HDAC inhibitors has been commonly observed (Suraweera, 2018). These findings have led to HDACis being explored as components of combination therapies, with the idea that they might enhance the therapeutic activity of other chemotherapeutic agents. One drawback of combining drugs for treatment is the increased potential for detrimental side effects. Some of this can be offset by examining the genetics of the treated patient. In order to use personalized medicine for screening patients who might receive combination therapy utilizing an HDAC inhibitor we attempted to identify all the possible enzymes that would need to be genetically evaluated in patient treated with different HDACi combinations.

Table 3 The number of different enzymes that are currently known to influence metabolism and thus efficacy of the drugs used to kill tumor cells with HDACi combination therapy.

HDAC Inhibitor Romidepsin Vorinostat

Belinostat

Combination 1 Combination 2

22

35

27

8

28

49

Combination 3

10

–

–

Drug

Enzymes (HUGO gene symbols) COYAPT3PA14B,3CYP3A5, CYP1A1, CYP2B6, CYP2C19, ABCB1, UGT1A1, UGT2B7, CYP2A6, CYP2C9, CYP3A4 U U G G T T 1 2 A B7 1 , , U U G G T T 2 1 B A 1 3 7 , UGT1A7, UGT1A8, UGT1A9, T 2 1 1, ,UdCCKK1, , CUDCAK, 2N, Th5CCN2T, 3C , MS AP KM1H, DC M1 , PNKT25, CR2R, MT Y1 M, S , CC YY PP 31 AA 52 ,, UC YG PT21BA64, , CUYGPT21CA98, C, YU PG2TC11A91, 0C, YUPG2TD26B, 7C , Y P 3 A 4 , UC YGPT12BB11,5C, YSPU2LCT81,AC1Y, PS1U9LAT 11E, C1Y, CPY2 PA26C, C9Y, CPY2PE11A, F1M, O 1 , FMO3, CES1, SULT2A1, ABCB1, ABCC2, ABCG2 C A T T R P7 1 B , O , G C S T T 1, OCT2, OCTN1, OCTN2, CTR2, ATP7A, CC YY PP 13 BA 17 ,, CC YY PP 21 C9 8A,1C, YAPB3CAB41,, CAYBPC3BA151, , A B C C 1 , A B C C 2 , ABCC10, SLCO1B3 CNBORS 11 ,, CNBORS32,, ANKORS 13 A, N1D, AUKFRS 21 ,CN3 D, PUOFRS,7X, DNHD,UNFQS 3O,1A, B C B 1 , A SO B D CC 1 1, ABCC2, ABCG2, CAT, GPX1,RALBP1, SLC22A16, C C Y Y P P 2 2 B C1 6 8 , C , C Y Y P P 3 2 A C 4 1 , C 9 YP3A5, CYP2C9, CYP2A6, CYP2C8 CA YB PC 3C A1 4, A, CBYCPC32A, A5 ,BCCYCP33, AA 7B ,CCCY1P02, EA1B, CAGB2C, BR1A, LABBPC1B, 1 1 , SLC22A3, SLCO1B3, SLCO1B1 R X hE ABCB1 R R N C M C FPGS, RFC, GGH

Conclusions

Romidepsin Belinostat Vorinostat 5-azacytidine

HDAC inhibitors are in their infancy in the chemotherapy arsenal. Not only is it difficult to identify the best way to use them in treatment they have not been completely studied for how the body metabolizes them in combination therapy. Current research suggests that one might have to investigate human variation in as many as 49 different enzymes in order to identify patients that will likely fail to respond or suffer severe adverse effects during treatment.

Lenalidomide Pralatrexate

Tamoxifen

References & Acknowledgments

Methods

Carboplatin

1. Dawson, Mark A. et al. Cancer Epigenetics: From Mechanism to Therapy. Cell, Volume 150, Issue 1, 12 – 27. 2. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone Deacetylase Inhibitors as Anticancer Drugs. Int J Mol Sci. 2017;18(7):1414. Published 2017 Jul 1. doi:10.3390/ijms18071414 3. Suraweera A, O'Byrne KJ, Richard DJ. Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Front Oncol. 2018 Mar 29. doi:10.3389/fonc.2018.00092 4. Kane M. Belinostat Therapy and UGT1A1 Genotype. 2023 Jul 20. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. 5. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK593302/

Paclitaxel

The HDACs reviewed were Romidepsin, Belinostat and Vorinostat and the drugs used in combination with HDACs included 5-azacytidine, lenalidomide, pralatrexate, tamoxifen, carboplatin, paclitaxel, doxorubicin, cyclophosphamide, vincristine. These terms were used in combination with terms like chemotherapy, genetics, personalized medicine, and drug metabolism in literature searches using PubMed and Google Scholar databases. Retrieved articles were examined for evidence of the use of HDAC inhibitors in cancer treatment in combination therapy and evidence of enzymes involved in the metabolism, development of side effects, or impacts on the efficacy of treatment.

Doxorubicin

Cyclophosphamide

Thank you to previous students whose papers contributed to this project through providing information on the enzymes for some of the combination drugs.

Vincristine

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