Key Points
- The new chemotherapeutic drug, AOH1996, inhibits a protein called proliferating cell nuclear antigen (PCNA) that is crucial to cancer cell DNA repair and replication.
- AOH1996 selectively kills cancer cells to suppress tumor growth in mice.
- Treating tumor-bearing mice with the chemotherapeutic agent CPT-11 alone or combined with AOH1996 increases their median survival by 34.6% and 55.4%, respectively.
Cell stress from DNA damage, which cancer cells must overcome to continue their replication and proliferation, represents a hallmark of cancer. Exploiting this cancer-associated feature has previously been dubbed an undruggable target to stop cancer in its path.
Published in Cell Chemical Biology, Malkas and colleagues from City of Hope in California reveal that a newly-identified small molecule drug called AOH1996 inhibits a vital protein for cancer cell DNA repair and replication called PCNA. In doing so, the drug kills cancer cells to suppress tumor growth without adversely affecting healthy cells in mice. Intriguingly, when combined with another drug that induces DNA damage called CPT-11, it increases tumor-bearing mouse median survival by 55.4%. With an ongoing phase I human trial already underway for AOH1996, these findings provide hope for eliminating multiple types of cancer without toxic side effects.
“No one has ever targeted PCNA as a therapeutic because it was viewed as ‘undruggable,’ but clearly City of Hope was able to develop an investigational medicine for a challenging protein target,” said Long Gu, PhD, a lead author of the study from City of Hope in a press release. “We discovered that PCNA is one of the potential causes of increased nucleic acid replication errors in cancer cells. Now that we know the problem area and can inhibit it, we will dig deeper to understand the process to develop more personalized, targeted cancer medicines.”
AOH1996 Selectively Kills Multiple Types of Cancer to Suppress Tumor Growth
After identifying AOH1996 as a PCNA inhibitor, Malkas and colleagues sought to find whether it increases toxicity against cancer cells when combined with other chemotherapeutic agents like cisplatin. The researchers treated human nerve cancer (neuroblastoma) cells with AOH1996 and cisplatin for 18 hours and found the combination drastically reduced the number of cancer cell colonies compared to cisplatin treatment alone, especially at higher cisplatin concentrations. These findings suggest that when combined with other chemotherapeutics, AOH1996 dramatically enhances the chemotherapeutic effect of killing off cancer cells.
Since AOH1996 showed promising toxic effects against cancer cells when combined with the chemotherapeutic cisplatin, Malkas and colleagues sought to find whether AOH1996 inhibits cancer in tumor-bearing mice. In three separate groups of mice, the City of Hope-based research team implanted human neuroblastoma, breast cancer, or lung cancer tumors. Compared to non-treated mice, AOH1996 significantly reduced the growth of tumors, especially at longer durations of about 30 days for each cancer type. These data provide evidence that AOH1996 inhibits cancer cell proliferation to suppress tumor growth.
To find whether AOH1996 combined with another effective DNA damage-inducing chemotherapeutic called CPT-11 increases lifespan, the researchers measured the survival durations of mice with implanted human neuroblastoma tumors. They found that the mice’s median survival increased about 34.6% with CPT-11 treatments alone and 55.4% when CPT-11 and AOH1996 treatments were combined. These results show that AOH1996 significantly increases tumor-bearing mouse lifespan when combined with the chemotherapeutic CPT-11.
“PCNA is like a major airline terminal hub containing multiple plane gates. Data suggests PCNA is uniquely altered in cancer cells, and this fact allowed us to design a drug that targeted only the form of PCNA in cancer cells. Our cancer-killing pill is like a snowstorm that closes a key airline hub, shutting down all flights in and out only in planes carrying cancer cells,” said Malkas, senior author of the study in a press release. “Results have been promising. AOH1996 can suppress tumor growth as a monotherapy or combination treatment in cell and animal models without resulting in toxicity. The investigational chemotherapeutic is currently in a Phase 1 clinical trial in humans at City of Hope.”
Human Trials Will Reveal Whether AOH1996 is the Holy Grail
Treatment Against Multiple Cancer Types The study shows the effectiveness of the PCNA protein inhibitor AOH1996 that reduces the abilities of cancer cells to repair damaged DNA and replicate. By inhibiting cancer cell DNA repair and replication, AOH1996 suppresses tumor growth without having toxic effects on healthy cells. The human trial at City of Hope will tell whether this small molecule drug is the breakthrough cancer therapy we have all been waiting for.
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