“Oral Chemotherapy”: Recent Breakthroughs in a Potential Cancer Treatment

A novel cancer-targeting drug has begun phase 1 of human trials. Current forms of chemotherapy are typically successful in killing fast-growing cancer cells but also impede the growth of healthy cells within the body. Unlike many of the current chemotherapy options which can produce toxicity in humans even at the therapeutic dose, the new drug known as AOH1996 has been found to selectively target and kill cancer cells while showing no signs of toxicity to non-malignant cells.(1) Named after Anna Olivia Healy, AOH1996 honors a young girl who lost her life due to a form of cancer known as neuroblastoma.(2) The research team is led by Linda Malka at City of Hope, a biotechnology company that serves as one of the foremost cancer research and treatment organizations in the United States. After nearly twenty years of research, AOH1996 has passed toxicity testing in both mice and dogs, clearing the drug to begin human trials.(3)

AOH1996 is an orally administered drug that works by targeting a protein called PCNA, or proliferating cell nuclear antigen. Through her research, Malka found an isoform of this protein, cancer-associated PCNA (caPCNA), to be an especially attractive protein to target due to its structure, which provides ample binding locations for other proteins involved in the DNA replication process.(3) When AOH1996 binds to a specific region in caPCNA, the protein’s interaction with RPB1, the large subunit of RNA polymerase II, is enhanced.(4) This action causes the RPB1 protein to be flagged for degradation. Consequently, PCNA dissociates from the actively transcribed chromatin regions, resulting in the accrual of double-stranded breaks in the DNA and effectively hindering the replication process of the targeted cancer cell.(5) Put more simply, AOH1996 is a PCNA inhibitor that selectively targets the caPCNAs found in cancer cells, restricting the cell replication process in the cancerous cells and leaving healthy cells alone.

A rise for concern came into play when beginning to test for AOH1996, questioning whether the drug would pose the same threat to non-malignant cells as it did to the cancer cells being targeted (as seen in current chemotherapy drugs). If this was found to be the case, the drug risks levels of toxicity, preventing the process of replication for healthy cells, which humans need for simple growth and survival. Common symptoms of toxicities caused by current chemotherapy drugs include fatigue, alopecia, gastrointestinal issues such as nausea and vomiting, and myelosuppression (bone marrow suppression) which could give rise to conditions such as anemia.(6) Through the initial phases of AOH1996 testing done on mice and dogs, AOH1996 was found to pass toxicity levels up to ten times its effective dose, indicating that healthy cells are not being targeted.(7)

Phase 1 clinical trials are testing the safety of AOH1996 for human patients with reoccurring all-solid tumors. This phase, being conducted at City of Hope Los Angeles, is expected to last roughly two years with a primary goal of establishing the maximum tolerated dose of the AOH1996 pill as well as assess its overall effectiveness.(8) The hope is that AOH1996 will one day be approved for combined use with other existing therapies, such as checkpoint inhibitors, that will result in enhanced destruction of cancer cells while maintaining the overall goal of limiting the harmful side effects experienced with many cancer treatments today.(2)

References

1. Journal of Clinical Oncology | Mechanistic Study of the Superior Anti-Cancer Properties of a First-in-Class Small Molecule Targeting PCNA by Long Gu; Robert Lingeman; Min Li; Robert Hickey; Yilun Liu; Linda Malkas

2. City of Hope | Cancer Center Announces First Patient Has Received City of Hope’s Novel, Potentially Cancer-Stopping Pill by Zed Logsdon

3. Science | A new Mode of Cancer Treatment by Derek Lowe

4. News Medical | New PCNA Inhibitor AOH1996 Shows Selective Cancer Cell Killings and Tumor Suppression Potential by Tarun Sai Lomte; Reviewed by Lily Ramsey LLM

5. Cell Chemical Biology | Small Molecule Targeting of Transcription-Replication Conflict for Selective Chemotherapy by Long Gu; Min Li; J. Jefferson P.Perry

6. National Library of Medicine | Cancer Chemotherapy by Muhammad T. Amjad; Anusha Chidharla; Anup Kasi

7. American Association for Cancer Research | Pharmacological Targeting of Transcription-Replication Conflict Leads to Anti-Cancer Efficacy With Minimal Side Effects in Preclinical Model by Long Gu; Caroline Li’ Rober Lingeman’ Robert J. Hickey’ Linda H. Malkas

8. U.S. National Library of Medicine | AOH1996 for the Treatment of Refractory Solid Tumors by Vincent Chung