Metastatic Colorectal Cancers in Mice Virtually Eliminated Using Immunotherapy & Experimental Drug Combo
A preclinical study by Weill Cornell Medicine investigators has shown how an experimental anticancer therapy could have promise as a potential treatment for an aggressive, spreading type of colorectal cancer. The researchers, led by Maria Diaz-Meco, PhD, and Jorge Moscat, PhD, who are both Homer T. Hirst III professors of oncology in pathology at Weill Cornell Medicine, showed that the accumulation of a molecule called hyaluronan is a critical step in forming mesenchymal colorectal cancer (mCRC) tumors, and demonstrated how treatment using an experimental pegylated hyaluronidase therapy (PEGPH20) that targets and breaks down hyaluronan shrank mCRC-like tumors in mice.
“We have unraveled one of the critical mechanisms driving this aggressive type of colorectal cancer, and we are proposing a potential therapy for patients who currently have few options,” said Moscat, who is vice chair for cell and cancer pathobiology in the department of pathology and laboratory medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “Our discovery also has important implications for preventing this type of colorectal cancer,” added Diaz-Meco, who is a member of the Meyer Cancer Center.
The scientists reported on their studies in Cancer Cell, in a paper titled, “Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a therapeutic vulnerability in mesenchymal colorectal cancer.”
Mesenchymal colorectal cancer accounts for about one-third of all colorectal cancers. Targeted immune therapies aren’t effective against this form of cancer because the environment inside the tumor keeps immune cells that would kill the tumor cells at bay. “Despite improvements in systemic treatment, the metastatic disease shows a dismal 5-year survival rate of only 12–14%,” the authors wrote.
A previous study by the team showed that patients with reduced levels of two enzymes called PKCz and PKCi are more likely to develop mCRC tumors and have worse prognoses. When the genes encoding these enzymes are shut off in mice, the animals develop mCRC-like tumors. As the authors noted, “ … we have recently reported that low levels of the atypical protein kinase Cs (aPKCs; PKCζ and PKCλ/ι) are drivers for the initiation and progression of mesenchymal CRC (mCRC) as well as for their resistance to ICB.” Moscat added, “Those two enzymes are the gatekeepers. When they are lost, it sets tumor formation in motion immediately.”
Using an animal model and single-cell analysis of their tumors, the team, including co-first authors Anxo Martinez-Ordoñez, PhD, a postdoctoral associate in pathology and laboratory medicine, and Angeles Duran, PhD, an assistant professor of research in pathology and laboratory medicine, showed that one of the first steps in the process is the accumulation of the glycosaminoglycan hyaluronan, which begins before the tumors form. The hyaluronan attracts connective tissue cells called fibroblasts. These cells encourage the development of the most aggressive type of tumor cells and shut down the immune system’s ability to kill the tumor cells, Moscat said.
In fact, the team pointed out, several laboratories are looking at anticancer strategies that target different molecules of the tumor microenvironment (TME) extracellular matrix, such as collagens and hyaluronan, rather than the cellular components. “The rationale behind this approach is that reducing the extracellular matrix barrier purportedly protecting the tumor would result in better access to chemotherapeutics and ICB [immune checkpoint blockade] treatments.”
The results are particularly exciting because liver metastases are common in patients with mCRC and are challenging to treat, Diaz-Meco explained and added, “Hyaluronidase makes the tumors susceptible to immunotherapy.” The team also identified biomarkers that might help identify which patients with mCRC would benefit from hyaluronidase therapy. “Evidence presented here in two mCRC mouse models establishes that low aPKC/HA-positive mCRC patients will benefit from PEGPH20-based treatment,” they wrote.
The researchers are working with clinical partners toward launching a human trial of hyaluronidase as a treatment for mCRC. Prior clinical evaluation of hyaluronidase as a potential treatment for pancreatic cancer (pancreatic ductal adenocarcinoma; PDAC) had demonstrated the drug to be safe with manageable side effects, but it wasn’t found to be effective against pancreatic cancer. Diaz-Meco said a better response in patients with mCRC is anticipated because, unlike pancreatic cancer, these tumors have immune cells that—while excluded from the core of the tumor—are present in its periphery and ready to be activated.
“A potential explanation for the discrepant findings of the lack of effect of monotherapy with PEGPH20 in PDAC as compared with the positive effects in mCRC may lie in the differences between the TME of these two types of tumors,” the team reasoned. “Thus, PDAC tumors are known to be immune-deserted, characterized by a paucity of T cells in either the parenchyma or the stroma of the tumor … In contrast, aPKC CRC tumors are immune-excluded and, therefore, characterized by the presence of abundant immune cells that do not penetrate the parenchyma of these tumors but instead are retained in the stroma that surrounds the tumor epithelium.”
Additionally, the dose that the team plans to test in patients with mCRC is equivalent to the amount used in the preclinical studies. Moscat explained that the preclinical studies on pancreatic cancer used much higher doses of the drug, which weren’t feasible for the human PDAC trial. “… it is important to emphasize that the dose of PEGPH20 utilized in the PDAC clinical trials was approximately 400-fold lower than the one used in PDAC preclinical models, indicating that to achieve clinical response in PDAC patients much higher hyaluronidase doses would be required, which will be unfeasible because of toxicity,” the team continued. “In marked contrast, we show here that mCRC is fully sensitive to the clinical doses of PEGPH20 (0.0375 mg/kg), which strongly suggests that perhaps PDAC was not the right type of neoplasia to be treated with PEGPH20, whereas a better response would be obtained in patients with mCRC.”
The investigators are in parallel looking for ways to prevent mCRC from occurring or spreading. They hope to learn how the guardian enzymes are lost prior to the onset of cancer, and if they can find treatments that block the production of hyaluronan to prevent cancer or its spread. Such treatments may be particularly beneficial for patients at high risk of colorectal cancer, such as those with ulcerative colitis or inflammatory bowel disease. “If you can block the process by removing hyaluronan, you can prevent tumor formation or its spread to the liver, making it easier to treat,” Moscat suggested.