In 30% of pancreatic cancers, MYC protein activity increases – playing a role in tumor growth. In order to genetically screen for such activity and develop treatments, clinicians need tumor samples. A team from Inserm suggests creating organoids from the small quantity of tumor cells taken from patients during diagnosis, making it possible to reconstitute an in vitro tumor within the space of two weeks.
With around 14,000 new cases each year in France and a similar number of deaths five years down the line, the prognosis of pancreatic cancer remains bleak. Generally detected at an advanced stage, it is difficult to treat, and its high level of molecular diversity demands personalized therapies which are essential for effective treatment.
In around 30% of cases, the MYC protein is overactivated in the tumor. This protein controls the expression of around 1,500 genes implicated in cell proliferation, metabolism and survival – a phenomenon which contributes to the progression of the cancer. While various drugs are being developed to target this abnormality, they still need to be administered to the right patients.
And therein lies the challenge for clinicians. Although they have a genetic test to screen for MYC overactivation, this can only be used in 15% of cases. The tumor sample needed for it is obtained surgically – but only 15% of patients undergo surgery. The operation is pointless in the remaining 85% of cases, and the researchers only have a small quantity of tumor cells at their disposal, which is taken by endoscopic ultrasound during diagnosis. While it is possible to increase their number by culturing these cells, they lose their in vivo acquired characteristics, which could skew the results of the genetic test. And while these cells could also be transferred to a mouse for proliferation and production of a tumor identical to that of the patient – making the genetic test possible – such a process takes months, rendering it incompatible with the urgency of treatment.
Tumors reconstituted in vitro
To address these difficulties, Juan Iovanna and his team* proposed using the tumor cells to create organoids, something which is already being done for other tissues. This involves reconstituting a mini organ in vitro from stem cells or slightly differentiated cells which self-organize within an appropriate culture medium and a 3D environment. The resulting architecture and functionalities of the organoid are very close to the organ in vivo. By applying this process to the tumor cells of 24 patients, the researchers were able to recreate – in vitro and within just two weeks – tumors corresponding to each patient. They could then screen for MYC overactivation and test two anti-MYC drugs that are currently in development. One of the drugs, NHWD870, has proven to be up to ten times more effective than its counterpart in bringing about tumor regression.
"We have demonstrated the proof-of-principle of the utility of organoids in tumor classification and drug testing in pancreatic cancer. Our next step is find markers predictive of response to the various drugs available, in order to administer the most appropriate treatments to patients. Ultimately, we hope to be able to transfer this to the clinical setting. While this technique demands specific resources and skills, it represents the best tool so far when it comes to progressing towards personalized medicine in this form of cancer", considers Iovanna.
*unit 1068 Inserm/CNRS/Paoli Calmettes Institute/Aix-Marseille Université, Pancreatic cancer team, Cancer Research Center of Marseille