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UC San Diego researchers identify new therapeutic approach to kill cancer cells



Epithelial cancers, such as lung and pancreas cancers, use the αβ3 molecule to gain drug resistance to standard cancer therapies and to become highly metastatic. In a paper published in Cancer Research, University of California San Diego School of Medicine researchers have identified a novel therapeutic approach in mouse models that halts drug resistance and progression by using a monoclonal antibody that induces the immune system to seek and kill αβ3-expressing cancer cells.

This antibody is designed to seek and destroy most stem-like, drug-resistant, aggressive tumor cells. It does this by building a bridge between tumor-associated macrophages and these highly aggressive tumor cells. What we have been able to observe in mice is that when we give this drug to drug-resistant tumors, it prolongs their response to standard of care and prevents their capacity to enter the blood stream. "

David Cheresh, PhD, Distinguished Professor and Vice Chair of Pathology, University of California San Diego School of Medicine

Using the αβ3 antibody LM609, Cheresh and his team exploited the expression of αβ3 receptors on tumor cells to redirect tumor-associated macrophages (TAMs) into recognizing and killing αβ3 expressing tumor cells.

During the study period, no tumor progression or drug resistance was detected while untreated animals developed tumor growth and metastasis. Research in mouse models focused on pancreatic and lung cancer cells treated in combination with LM609 and the EGFR inhibitor erlotinib. But the antibody is expected to work in combination with various drugs currently used to treat cancer patients, said Cheresh.

"We have observed a very significant link between the appearance of αβ3 expressing tumors and the appearance of tumor-associated macrophages," said Cheresh, associate director of innovation and industry alliances at UC San Diego Moores Cancer Center. "Normally, the appearance of tumor-associated macrophages promotes tumor growth and metastasis. However, our antibody arms these macrophages to join our fight against cancer."

Macrophages are specialized immune cells that promote tissue inflammation, stimulate the immune system and rid the body of foreign debris, including cancer cells. TAMs instead create a pro-tumor environment that accelerates tumor growth, angiogenesis (the development of new blood vessels to support the tumor) and suppresses immune recognition of the tumor by the host immune response.

As tumors progress, the abundance of TAMs increases, allowing the cancer to become more aggressive and spread. As tumors become drug-resistant, αβ3 appears on cell surfaces.

The Cheresh lab has previously discovered that αβ3 is upregulated in various cells during normal wound repair and in cancer cells as cancer becomes invasive. In both cases, this molecule triggers cells to enter a stress-tolerant state. In normal epithelial cells, this state enables them to initiate tissue remodeling, such as healing. In cancer, it allows cells to become drug-resistant and highly metastatic.

The current study revealed a new approach to induce TAMs to reverse course, killing cancer cells rather than supporting them. The antibody prompts these macrophages to begin killing tumor cells through a mechanism known as antibody-dependent cytotoxicity (ADCC).

"These results were initially unexpected since macrophages usually destroy cells via phagocytosis, a process that involves literally devouring the foreign or target cell," said Cheresh, a faculty member of the Sanford Consortium for Regenerative Medicine. "Also, ADCC is typically known to be induced by natural killer cells, but we have seen very few of these NK cells in late-stage, drug-resistant cancers."

"We believe that the effectiveness of this antibody is based on three things: Its ability to recognize drug-resistant cancers. Its ability to bind to a particular receptor on tumor-associated macrophages. And its capacity to induce ADCC of these highly aggressive tumor cells. "

The protein CD47, which is found in many cells in the body and is often hacked by cancer cells, tells macrophages not to eat these cells. The αv3 antibody bypasses CD47 "do not eat me signal" by inducing ADCC as opposed to phagocytosis.

"In our studies, macrophages are not killed through phagocytosis that would be blocked by the appearance of CD47 on the target cell. Rather, we are inducing macrophage to kill its target cell by its ability to mediate ADCC. The therapeutic antibody we are utilizing is bridging the macrophage to the αβ3-expressing tumor cell as a target. When this occurs it releases a cytotoxic substance that kills the tumor cell. "

The team is currently producing a humanized version of this antibody that Cheresh hopes will do in humans what LM609 does in mice.

Source:

University of California San Diego School of Medicine


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