Preclinical studies have identified potential treatments for metastatic colon cancer

According to a new study by Weill Cornell Medical researchers, an experimental therapy has shown promise
in preclinical models for treating an aggressive and spreading colorectal cancer.

Mesenchymal colorectal cancer (mCRC) accounts for about one-third
of all colorectal cancers.
Targeted immunotherapy is ineffective against this type of cancer because the environment inside the tumor prevents immune cells from killing
the tumor cells.
But the team led by Dr.
Maria Diaz-Meco and Dr.
Jorge Moscat, both Homer T.
Hirst III professors of oncology pathology at Weill Cornell Medical College, in a study published Dec.
15 in Cancer Cells found that the accumulation of a molecule called hyaluronic acid is a key step
in the formation of mCRC tumors.
They also demonstrated that an experimental therapy targeting hyaluronic acid could shrink mcrc-like tumors
in mice.

"We have revealed one of the key mechanisms driving this aggressive colorectal cancer, and we are proposing a potential treatment for patients who currently have few options," said
Dr.
Moscat, vice chair of cell and cancer pathobiology in the Department of Pathology and Laboratory Medicine and a member of the Sandra and Edward Mayer Cancer Center at Weill Cornell Medical College.

"Our findings also have important implications for preventing this type of colorectal cancer," said Dr.
Diaz-Meco, who is also a member of
the Meyer Cancer Center.

A previous study by the team showed that patients with reduced levels of two enzymes, PKCz and PKCi, were more likely to develop mCRC tumors with a worse
prognosis.
When the genes encoding these enzymes were turned off in mice, the animals developed tumors that resembled MCRC
.

"These two enzymes are gatekeepers," Dr.
Moscat said
.
"When they're lost, they immediately promote tumor formation
.
"

Using animal models and single-cell analysis of their tumors, the team, including co-first author Dr.
Martinez-Ordoñez, Ph.
D.
, postdoctoral fellow in pathology and laboratory medicine and assistant professor of pathology and laboratory medicine, showed that the first step in this process is the accumulation of hyaluronic acid, which begins before
tumor formation.
Hyaluronic acid attracts connective tissue cells
called fibroblasts.
Dr.
Moscat said these cells promote the development of the most aggressive tumor cells and shut down the immune system's ability to
kill tumor cells.

But treating mice with MCRC-like tumors with an experimental therapy called hyaluronidase, which breaks down hyaluronic acid, shrinks tumors and allows immune cells to attack tumor cells
.
Combined with targeted immunotherapy, anti-PD-L1 and anti-CTLA-4 antibodies with hyaluronidase virtually eradicated mCRC tumors
that had spread to the liver in animals.
Dr.
Diaz-Meco explains that this is particularly exciting because liver metastases are common in patients with mCRC and treatment is challenging
.

"Hyaluronidase sensitizes tumors to immunotherapy," Dr.
Diaz-Mayco said
.

The team also identified biomarkers that may help determine which mCRC patients will benefit from hyaluronidase treatment
.
They are currently conducting clinical trials with clinical
partners.
Clinical trials of hyaluronidase as a treatment for pancreatic cancer have shown that the drug is safe and side effects are manageable
.
But this therapy is not effective
for pancreatic cancer.
Dr.
Diaz-Mayco said they expect better responses from mCRC patients because, unlike pancreatic cancer, these tumors have immune cells that, although not at the core of the tumor, are present on the periphery of the tumor and ready to be activated
.
In addition, the doses they plan to test in patients with mCRC are comparable
to those used in preclinical studies.
Dr.
Moscat explained that preclinical studies of pancreatic cancer use much higher drug doses, which is not feasible
in human trials.

The group is also looking for ways
to prevent mCRC from occurring or spreading.
They want to understand how guardian enzymes are lost before cancer occurs, and whether they can find treatments that block hyaluronic acid production to prevent cancer or its spread
.
This treatment may be particularly beneficial
for people at high risk of colorectal cancer such as ulcerative colitis or inflammatory bowel disease.

"If you can stop this process by removing hyaluronic acid, you can prevent tumors from forming or spreading to the liver, making treatment easier," Dr.
Moscat said
.