A recent study conducted by scientists at Duke-NUS Medical School has uncovered the reason behind the resistance of certain pancreatic and colorectal tumors to targeted anti-Wnt drugs. This discovery provides new hope for patients with treatment-resistant cancers and offers potential solutions for overcoming this resistance. The findings, published in Science Advances, reveal a promising new avenue for cancer therapy and a potential screening tool for identifying patients who may not benefit from these new drugs.that in some cases, the growth of tumors is actually accelerated by the use of these drugs,” shared Dr. Dean Tang, Deputy Director of the Cancer and Stem Cell Biology Program at Duke-NUS Medical School and senior author of the study. “This is a significant obstacle that needs to be addressed before Wnt inhibitors can be widely used as a treatment for gastrointestinal cancers.”
The study, which was conducted by researchers from Duke-NUS and the Agency for Science, Technology and Research (A*STAR) in Singapore, used patient-derived models of colorectal cancer to investigate the effects of Wnt inhibitors. The findings revealed that while the drugs were effective in slowing down the growth of some tumors, they actually accelerated the growth of others. This suggests that a “one-size-fits-all” approach to Wnt inhibitors may not be the best strategy for treating gastrointestinal cancers.
“Our study highlights the importance of developing personalized therapies for gastrointestinal cancers, rather than relying on a one-size-fits-all approach,” explained Dr. Tang. “By identifying the specific molecular characteristics of each patient’s tumor, we can develop targeted therapies that are more effective and less likely to cause unintended side effects.”
The researchers now plan to further investigate the molecular mechanisms underlying the different responses to Wnt inhibitors in colorectal cancer, with the goal of developing more effective and personalized treatments for this deadly disease. Their findings could have important implications for the future of cancer therapy, offering hope to patients with gastrointestinal cancers who may benefit from personalized treatments tailored to their specific molecular profile.
Dr. Zhong Zheng, who conducted the research as a postdoctoral fellow at Duke-NUS’ Cancer & Stem Cell Biology Programme, emphasized the importance of understanding why some cancer cells are resistant to treatment. “Understanding the mechanisms behind this resistance is crucial for personalized treatments for patients when the drugs don’t slow tumor growth at all,” said Dr. Zheng. The study focused on colorectal and pancreatic cancers with a hyperactive Wnt pathway. Dr. Zheng and Professor David Virshup, who leads the Programme at Duke-NUS, used their Wnt inhibiting drug ETC-159 to assess the cancer cells’ responsiveness. The drug’s efficacy had been established in preclinical models. The researchers analyzed genetics data to better understand the intrinsic resistance in certain cancer cells.In both responsive and non-responsive tumors, researchers found that a second mutation in a different gene, called FBXW7, causes cancer cells to become resistant to Wnt-blocking drugs. FBXW7 mutations are present in approximately 15 percent of colorectal cancers. Dr. Zhong explained that these mutations change the behavior of the cancer cells, causing them to become indifferent to the Wnt pathway, rendering the drugs ineffective. Testing tumors for FBXW7 genetic mutations could prevent many patients from receiving useless treatment, making it a potential biomarker and a target for new cancer treatments.
Senior author Prof Virshup emphasized the importance of predicting drug resistance in precision oncology. The study uncovered how cancers can bypass dependencies on Wnt signaling, providing a strong basis for further research and development.
Dr. Zhong stated that the discovery opens up potential treatment options by targeting alternative pathways activated by the FBXW7 mutation to combat drug resistance.
This latest research builds upon previous work by the scientists on the mechanisms behind pancreatic cancers developing resistance to treatment. Collectively, these findings enhance our knowledge of how cancers adapt and seek out alternative pathways.Routes to grow and survive.
The discovery of FBXW7 and its role in Wnt inhibitor-resistant tumors is a step forward in finding more precise therapeutic targets. This brings us closer to the promise of personalized therapies. The researchers also found that these resistant tumors can be treated with an experimental drug called dinaciclib. The next step is to explore the potential of dinaciclib as a standalone treatment or in combination with other agents for these cancers.
Prof Virshup, the lead researcher, stated, “Our ultimate goal is to help patients with fully resistant tumors by targeting the alternate cancer pathways unleashed by FBXW7 mutations.” The hope is to translate these findings into effective treatments for patients.
“Our discoveries will lead to more customized and effective treatment approaches.”
“This study demonstrates the highly practical nature of the fundamental scientific research carried out at Duke-NUS. Cancers are known for their wide-ranging characteristics, and it’s crucial for us to comprehend and chart that variety so that we can provide personalized treatment that actually works for the individual, instead of subjecting patients to unnecessary treatments that won’t be effective for them,” explained Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS. “This research is another significant stride in our efforts to turn every cancer into a manageable condition, and the team’s work serves as a prime example of this.”The commitment to providing better treatments for patients is a top priority.
[1] In Singapore, colorectal cancer is the second most commonly diagnosed cancer for both men and women. Meanwhile, pancreatic cancer ranks as the 10th most common cancer among men in Singapore. According to the World Health Organisation, there were over 1.9 million new cases of colorectal cancer diagnosed globally in 2020 alone.
[2] Duke-NUS and A*STAR have collaborated to create a Wnt inhibitor called ETC-159, which is a product of Singapore. This inhibitor is currently undergoing early phase clinical trials.