A recent preclinical trial using mice reveals that the precancerous cells of the pancreas can be disposed before they can develop into a tumor. Application of an experimental therapy to attack microscopic precancerous lesions in the pancreas was shown to increase survival in mouse models of a pancreatic ductal adenocarcinoma (PDAC) by nearly 2 times even when the same therapy was administered when the cancer was already present.
The study was carried out under the leadership of physician-scientists of the Perelman school of medicine in the University of Pennsylvania and Abramson cancer center of Penn medicine, which is released to date in Science.
It is also the first instance that scientists have demonstrated that a medical intervention could prevent growth of pre-cancerous lesions in the pancreas before it becomes pancreatic cancer and this is a good indication to the growing area of cancer interception.
I believe that the next age of cancer treatment will be interception, and I am confident that such an endeavor will be developed by cancer treatment experts like Robert Vonderheide, the director of the Abramson Cancer Center. Pancreatic cancer has had a stubborn poor prognosis, scarce treatment options as well as no tested screening and prevention measures. And should we be able to get a means of intercepting it–of detecting and counteracting abnormalities in their first beginnings of malignancy, it would be an issue game changer.
Cancer interception is different to cancer prevention.
Contrary to prevention approaches, like HPV vaccination or ceasing a smoking habit, which seek to ensure that the cancer never develops at all, cancer interception focuses on the first stages of a cell becoming malignant. Colonoscopy can be taken to illustrate an instance of a mechanical interception where the precancerous polyps are removed before they turn into colorectal cancer. Since the harder the malignancy is to treat, the larger it is, the idea of curing the malignant growths before they become cancer is quite a logical one in theory, yet challenging to be proven.
“The paper is a preclinical evidence-of-concept demonstrating that medical cancer interception is better than treatment of a diagnosis,” said the lead author, Minh Than, a clinical and research fellow in the field of Hematology-Oncology. “This research demonstrates the strength of using a proactive approach to cancer, as opposed to a reactive one. This will be interesting to test in our patients in the second stage of this work.”
RAS inhibition is an efficient way of intercepting cancer in mice.
In this research, the researchers employed two experimental inhibitors that are directed to the cancer causing gene, KRAS. KRAS mutations that cause more than 90 percent of pancreatic cancers are the most frequent cancer-causing gene mutation found in all cancers and has been traditionally thought to be undruggable.
The first KRAS inhibitor was approved in 2021 to treat non-small cell lung cancer and since that time, there have been additional KRAS inhibitors entering clinical trials treating various types of cancer, such as pancreatic cancer.
The majority of PDAC tumors are seen to be as a result of microscopic lesions referred to as PanINs (pancreatic intraepithelial neoplasias), which are too small to be detected through scans, and nearly all the PanINs have KRAS mutations. PanINs are typical in adult pancreases, but the few who become cancer only rarely; researchers are yet to understand the reason behind this unusual malignant conversion. Though this study did not aim at learning the biology or at better detection of PanINs, the research team hypothesized that removing these early lesions with the help of KRAS inhibitors, regardless of their awareness of which have malignant potential, would be an effective approach to preventing their ever transition into PDAC.
The group evaluated the two compounds identified by Revolution Medicines whose scientists participated in the analysis.
Both the compounds are meant to block the RAS when it is in the active or ON form and mediate cancer growth. RMC-9945 is a preclinical tool compound a selective inhibitor of KRAS G12D, the most frequent type of KRAS mutation in pancreatic cancer and it is one of a class of oral RAS(ON) G12D-selective inhibitors, such as the investigational drug candidate zoldonrasib (RMC-9805). RMC-7977 is a compound of clinical tool that targets several variants of RAS(ON) and is an example of oral RAS(ON) multi-selective inhibitors that contains an investigational drug candidate daraxonrasib (RMC-6236).
The research team considered the gold standard in the preclinical assessment of potential therapies of PDAC using an immunocompatible mouse model that was developed by Penn and that had a healthy and functional immune system. They firstly laid a baseline of PanIN to PDAC progression development in a control group. Then they treated an intervention group to either RMC-9945 or RMC-7977, following PanIN development, but prior to tumor development. It was also found that the reduction of the precancerous lesions occurred after 10 days of treatment and further reduced upon 28 days of treatment. In this milestone, Tumors took longer to form, and the survival of the mice was higher than in those mice that were not given the intervention. The team then discovered that extended administration of RMC-7977 to PanIN-bearing mice increased median overall survival time threefold in comparison with untreated control group with PanINs. Lastly, the intervention group that was treated earlier before the development of tumors had almost twice the lifespan compared to the group of mice that was treated after tumor development.
Further clinical trial to target high-risk patients.
The direct analogy in this paper places PanINs on the map as the possible targets of intercepting cancer and opens the field to investigate KRAS inhibitors in a new context, co-corresponding author Ben Stanger, MD, PhD, the Hanna Wise Professor in Cancer Research and director of the Penn Pancreatic Cancer Research Center. Nevertheless, due to the fact that PanINs are not visible on imaging tests and we are dealing with the case of treating people who are not cancer-diagnosed, we should seriously consider how to transfer this preclinical study to the appropriate population so that human trials can be conducted.
The team seeks to apply the research to a clinical trial where it targets high-risk patients who are already under monitoring over growths that exceed PanINs in size but still at a low risk of cancer but are usually removed once they attain a specific size. Should such a strategy proceed, the research group believes that it would be most relevant to people with a genetic susceptibility to pancreatic cancer, such as BRCA1, BRCA2, or PALB2 gene mutations, hereditary pancreatitis, precancerous cysts, or other high-risk factors. Eventually, the strategy could be considered for a broader range of individuals at intermediate risk.