Investigational Compound from Chinese Tree Bark Shows Potential as Treatment for Pancreatic Cancer

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A new compound found in the bark of a rare Chinese tree, called FL118, has powerful anticancer properties and a low toxicity profile. This is what researchers at Roswell Park Comprehensive Cancer Center observed in a study funded by grants from the National Cancer Institute and by donations to Roswell Park The results of their study outlining the effect of the new compound, were published in the October issue of  Journal of Experimental & Clinical Cancer Research.[1]

Pancreatic ductal adenocarcinoma or PDAC, the most common type of pancreatic cancer, is an extremely difficult to treat disease. Complete surgical removal of the tumor is one of the few options patients have as a chance for cure. However, on average, 80-90% of patients have a disease that is surgically incurable at the time of clinical presentation.

And even with an aggressive chemotherapeutic approach, only 6% to 8% of patients will survive 5 years beyond the time of diagnosis.

Chemotherapeutic approach
A chemotherapeutic approach may include include a combination therapy of gemcitabine (gemzar®; Eli Lilly) and nab-paclitaxel (albumin-bound paclitaxel; Abraxane®; Abraxis Bioscience, a wholly owned subsidiary of Celgene Corporation) as a first-line treatment for PDAC.

Other combination treatment options may include gemcitabine-cisplatin, gemcitabine-oxaliplatin and FOLFIRINOX (a combination of 5-Fu, leucovorin, irinotecan, and oxaliplatin). However, due to the possible serious toxicity of the FOLFIRINOX regimen, this option is only used as an aggressive treatment option for carefully selected patients.

Challenge
The biggest challenges in the treatment pancreatic tumors is that they are very dense. And this makes the delivery of cancer-fighting drugs very challenging. Another major challenge is caused by the fact that most tumors develop chemoresistance (resistance to treatment). This may, in both cases, result in desmoplasia, the growth of fibrous or connective tissue in which the interactions between tumor cells and stromal cells may play a crucial role in the pathobiology of pancreatic cancer.[2]  As a result, there is a major unmet need in the treatment of pancreatic cancer.

Camptothecin (CPT) has a planar pentacyclic ring structure, that includes a pyrrolo[3,4-β]-quinoline moiety (rings A, B and C), conjugated pyridone moiety (ring D) and one chiral center at position 20 within the alpha-hydroxy lactone ring with (S) configuration (the E-ring). Its planar structure is thought to be one of the most important factors in topoisomerase inhibition.
Natural derived compound
Camptothecin (CPT), an alkaloid isolated from the bark of the Chinese tree, Camptotheca acuminata, has, for centuries, been used in traditional Chinese medicine. The drug was first isolated more than 50 years ago by M. E. Wall and M. C. Wani in systematic screening of natural products for use as an anticancer agent.

Although several thousand synthetic camptothecin analogues have since been developed and tested, only two of them — irinotecan (Camptosar®; Pfizer and Onivyde®;Ipsen Biopharmaceuticals) and topotecan (Hycamtin®; Novartis) — have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer.

Both irinotecan and topotecan target topoisomerase I (TOP1), a protein critical for the growth and spread of cancer cells.  But TOP1 is also needed for renewal and growth of normal, healthy, tissue.  As a result, these highly toxic agents are limiting in how they can be used in the treatment of cancer patients.

Novel camptothecin analogue
A team of Roswell Park researchers led by Fengzhi Li, Ph.D, Associate Professor of Oncology in the Department of Pharmacology and Therapeutics, previously found that a novel camptothecin analogue they named FL118, which does not use TOP1 as its anticancer therapeutic target, effectively eliminated human colorectal and head & neck tumors that had become resistant to the two FDA-approved camptothecin compounds irinotecan and topotecan.

Photo 1.0: Fengzhi Li, Ph.D Associate Professor of Oncology Department of Pharmacology and Therapeutics Member, Molecular Pharmacology and Cancer Therapeutics Graduate Program Member, Experimental Therapeutics Cancer Center Support Grant Program Member, GI Disease Site Research Group at Roswell Park Cancer Institute Roswell Park Comprehensive Cancer Center.

Encouraged by these results, Li and his team tested the effectiveness of FL118 in preclinical pancreatic cancer models. In the current study, the researchers found that FL118, either alone or in combination with other chemotherapeutic agents, preferentially killed drug-resistant cancer cells and reduced the formation of new tumorspheres by killing cancer stem cells.

When used alone, FL118 effectively eliminated pancreatic tumors and, when used in combination with the first-line pancreatic cancer drug gemcitabine, FL118 killed tumors that were previously resistant to both gemcitabine and FL118, suggesting that the compound may help overcome resistance to a broad range of treatments.

Treatment resistance is a major concern because it paves the way to cancer cell metastasis. In turn, metastasis is a a concern since pancreatic cancer patients are often diagnosed with metastatic disease.

One of the key reasons why FL118 may be able to overcome treatment resistance is the fact that the investigational compound is not a substrate for drug-resistant factors such as ABCG2/BCRP* and and MDR1/Pgp which are well-established efflux pumps for TOP1 inhibitors irinotecan and topotecan.

Because FL118 is able to bypass ABCG2 resistance, it may be a potentially effective anticancer agent. In addition, the researchers observed that desmoplasia may not prevent FL118 from reaching therapeutic levels in the tumor microenvironment and within cancer cells. These observations, combined with the fact that FL118 did not produce the signs of toxicity common to other camptothecin-based agents and the fact that the agent was generally well tolerated at therapeutic dose levels, is, according to the researchers, very encouraging.

Unmet medical need
“Drugs that can more effectively reach and eliminate pancreatic tumors are urgently needed to treat this devastating disease,” Li said, who is senior author on the new study.

“FL118’s high anticancer efficacy, along with its favorable toxicology profile, is consistent with the fact that this drug targets several key proteins involved in pancreatic cancer progression and treatment resistance,” he added.

“Our study provides strong support for the development of FL118-based therapies for pancreatic cancer, especially in patients who are resistant to current treatment,” observed Xinjiang Wang, Ph.D, Associate Professor, Department of Pharmacology and Therapeutics at Roswell Park Cancer Institute Roswell Park Comprehensive Cancer Center and a corresponding author of the study.

“We believe that FL118 is promising new drug that can be further developed for the treatment of not only pancreatic cancer but also other types, such as colorectal cancer,” Wang concluded.

The researchers plan to develop a clinical study based on these findings.

Reference
[1] Ling X1, Wu W, Fan C, Xu C, Liao J, Rich LJ, Huang RY, et al. An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer. J Exp Clin Cancer Res. 2018 Oct 3;37(1):240. doi: 10.1186/s13046-018-0899-8.
[2] Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, Ramm GA, et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas. 2004 Oct;29(3):179-87.


*ATP-binding cassette subfamily G member 2 (ABCG2), an ATP-binding cassette (ABC) transporter identified as a molecular cause of multidrug resistance (MDR) in diverse cancer cells/Breast cancer resistance protein (BCRP).

Last Editorial Review: November 7, 2018

Featured Image: Pancreatic Cancer Cells. Courtesy: © 2018 Fotolia. Used with permission. Photo 1.0: Fengzhi Li, Ph.D Associate Professor of Oncology Department of Pharmacology and Therapeutics Member, Molecular Pharmacology and Cancer Therapeutics Graduate Program Member, Experimental Therapeutics Cancer Center Support Grant Program Member, GI Disease Site Research Group at Roswell Park Cancer Institute Roswell Park Comprehensive Cancer Center.   Courtesy: © 2018 Roswell Park Cancer Institute Roswell Park Comprehensive Cancer Center. Used with permission.

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