A new, chemically modified cancerdrug shows promising effects against pancreatic tumors, according to a study published recently in eLife.
Pancreatic cancer is both difficult to diagnose and difficult to treat. It is often not identified until it has progressed to an advanced stage, when patients are no longer eligible for surgical treatment.
Because of this, pancreatic cancer is the 5th leading cause of cancer deaths in the United States. New treatments, especially for late-stage pancreatic cancer, are urgently needed.
A team of researchers led by Anita S. Chong, PhD, Professor of Surgery at the University of Chicago, in collaboration with Cinkate Pharmaceutical Corp., recently tested a new cancer drug, called CK21, on patient-derived pancreatic tumor organoids and pancreatic tumors in mice. Organoids are 3D cell cultures that researchers use to study miniature organs in a dish. They also used genetic sequencing technology to uncover the mechanism CK21 uses to kill tumor cells.
Efficiency of CK21 in eliminating pancreatic tumors
CK21 is a chemically altered form of triptolide, a natural product which was originally extracted from a traditional Chinese herb, the Thunder God Vine. This herb was frequently used to treat symptoms of rheumatoid arthritis and lupus, and triptolide itself has potent anti-tumor effects. However, it can also cause serious, toxic side effects.
Cinkate Pharmaceutical developed CK21 as a pro-drug — a medication that the body converts into a pharmacologically active drug after it is administered — to overcome difficulties in drug delivery and prevent toxic side effects. They hoped these changes would improve its ability to reach and kill cancer cells while avoiding damage to healthy organs.
Qiaomu Tian, PhD, a post-doctoral researcher working under the guidance of Chong at the University of Chicago, tested the effects of CK21 on pancreatic tumors in mice. The first step was to identify a dose of CK21 that effectively killed cancer cells, but that did not show any signs of organ toxicity in mice.
“It surprised me that this drug seemed very, very safe,” said Tian.
Even when the cancer metastasized, it still worked
Then, mice with pancreatic tumors were given daily treatments of CK21; these mice saw significant reduction in tumor growth, with all the mice eliminating the tumor entirely. To simulate late-stage disease, mice with pancreatic tumors were allowed to progress until the tumors were large before starting treatment.
“We provided treatment to see if we could rescue them,” said Tian.
Still, CK21 was effective at reducing tumor size and even achieving remission in a few mice. Tian monitored them for six months to make sure the tumor did not come back.
Chong was surprised by the impressive results.
“Even when the cancer metastasized, it still worked," Chong said.
The location and size of the tumors were monitored by imaging, and most untreated mice developed metastatic disease, while the CK-21-treated mice did not.
Mechanism underlying CK21 action
Tian then used sequencing techniques to understand how CK21 killed pancreatic tumor cells. One of the effects of CK21 is inhibition of NF-kB, which is an important protein that regulates immune cell function. Importantly, treatment with CK21 did not seem to affect T-cell ability to kill tumor cells. This is impactful as it may ensure that CK21 would not interfere with the body’s immune response or potential immunotherapy treatments.
"It is ideal that if you have a chemotherapy that is not strongly immunosuppressive, then the patient has a chance to launch their own immunity against the remaining tumor cells,” Tian said, emphasizing the importance of maintaining the patient’s natural immune system.
Another effect of CK21 on tumor cells was a decrease in a protein called BCL-2. BCL-2 is part of a family of proteins that controls cell survival and cell death. Too little BCL-2 in the cancer cells can cause them to die by affecting their mitochondria.
“Even at 12 hours, there was a lot of transcriptional upregulation and downregulation of these pathways that implied mitochondrial damage, so that was pretty definitive,” Chong said.
CK1 as a future potential drug in clinics
Sometimes, there are differences in the way a drug affects humans compared to the effects it has in mice. However, sequencing showed similarities in the pathways affected by CK21 on mouse pancreatic tumors and tumor organoids created from patient samples. This is promising for future testing of CK21 in human clinical trials.
CK21 is currently in first-in-human cancer trials in China. Both Chong and Tian are cautiously optimistic, hoping to see the results of their research translate to successful clinical trials.
Chong said, “If this drug works as well in humans as in mice, it will bring a new class of compounds to the treatment of pancreatic cancer.”
Replicating results from animal studies in clinical trials is always challenging, Tian explains, but “CK21 has a chance.”
The study, “A novel triptolide analog downregulates NF-kB and induces mitochondrial apoptosis pathways in human pancreatic cancer,” was funded by Cinkate Pharmaceutical Corp., which also provided CK-21 for the work. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Additional study authors included Peng Zhang, Bo Qiu, and Fei Xiao from Cinkate; Melissa L. Fishel and Karen E. Pollok from Indiana University in Indianapolis; and Yihan Wang, Youhui Si, Dengping Yin, and Christopher R. Weber from the University of Chicago.
