Feature

Researchers uncover ‘novel drug target for glioblastoma’

Justin Lathia, PhD
Justin Lathia

An international study of glioblastoma revealed a cellular pathway that appears to contribute to glioma stem cell spread and proliferation.

“These findings are exciting because they put forth a new paradigm for glioma stem cell regulation,” Justin Lathia, PhD, vice chair of the department of cardiovascular and metabolic sciences at Lerner Research Institute of Cleveland Clinic, said in a press release. “This pathway shows that glioma stem cells’ ability to access key nutrients in their surrounding microenvironment, by way of ADAMDEC1, is integral for their maintenance and spread. Finding a way to interrupt this feedback loop will be important for treating glioblastoma.”

Previous research has shown that when the protein fibroblast growth factor 2 (FGF2) is active, it contributes to glioma stem cell self-renewal and tumor growth. However, researchers lacked understanding of how this process occurs.

For this reason, Lathia and colleagues sought to identify how glioblastoma cancer stem cells maintain their stemness. The researchers found FGF2 is a key intermediary in the multistep, pro-cancer signaling loop, and that “turning off” FGF2 potentially could prevent glioblastoma progression.

Healio spoke with Lathia about what led to this research, what he and colleagues found and what subsequent research will entail.

Question: What prompted this research?

Answer: For a long time, the field has known of a cancer stem cell population in advanced cancers, including glioblastoma. We have always wondered if there are communication mechanisms or ways that cancer stem cells can interact with their surrounding microenvironment for their benefit. We felt an unresolved question existed in the field about how cancer stem cells access additional nutrients in the microenvironment. We know from normal brain development that a lot of key growth factors are embedded in the matrix that surrounds the cells, but how the cells can gain access to the trapped growth factors remained unknown.

Q: How did you conduct the study?

A: We used a lot of human-derived glioblastoma samples from resected tumors. Through molecular biology approaches, we altered levels of the enzyme that we were interested in, and we used a series of preclinical animal models. We used a clinical grade inhibitor against the growth factor pathway that interested us to confirm the relevance of what we observed.

Q: What did you find?

A: Cancer stem cells produce an enzyme, ADAMDEC1, that they shed, which liberates key growth factors for the benefit of the cancer stem cells. We identified the interaction between ADAMDEC1 and FGF2 as a novel drug target for glioblastoma. Therapeutically targeting this interaction may be key to interrupting this cancer-driving loop. With standard treatment, median survival for adults with glioblastoma is only between 11 months and 15 months, and recurrence is common. New therapies are greatly needed.

Q: What are the clinical implications of the findings?

A: If we can harness this inhibitor, we may be able to leverage it into a clinical trial. This study also sheds light on other molecular targets that can be developed, which other investigator teams at Cleveland Clinic are studying.

Q: What will subsequent research entail?

A: We want to see if we can develop therapies and get them into clinic faster based on this information, whether that involves targeting the enzyme or the growth factor signaling pathway. We also realize that although the cancer stem cells can secrete ADAMDEC1 and liberate growth factors, those growth factors can also influence nontumor cells in the microenvironment, so it may change the inflammatory state of the tumor. These tumors tend to be skewed toward an anti-inflammatory, pro-tumorigenic state, and we think a lot of this is driven by the set of growth factors being processed. We are trying to better understand the additional communication outside of the cancer stem cell secreting a factor for its own benefit. We think that surrounding cells may be influenced, as well, and we are testing this hypothesis.

Q: Is there anything else that you would like to mention?

A: This study is being co-led by myself, as well as a group in Wales, so it is a multinational collaboration. – by Jennifer Southall

Reference:

Jimenez-Pascual A, et al. Cancer Discov. 2019;doi:10.1158/2159-8290.CD-18-1308.

For more information:

Justin Lathia, PhD, can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: lathiaj@ccf.org.

Disclosures: The study was funded in part by the Lisa Dean Moseley Foundation. Lathia reports no relevant financial disclosures.

 

Justin Lathia, PhD
Justin Lathia

An international study of glioblastoma revealed a cellular pathway that appears to contribute to glioma stem cell spread and proliferation.

“These findings are exciting because they put forth a new paradigm for glioma stem cell regulation,” Justin Lathia, PhD, vice chair of the department of cardiovascular and metabolic sciences at Lerner Research Institute of Cleveland Clinic, said in a press release. “This pathway shows that glioma stem cells’ ability to access key nutrients in their surrounding microenvironment, by way of ADAMDEC1, is integral for their maintenance and spread. Finding a way to interrupt this feedback loop will be important for treating glioblastoma.”

Previous research has shown that when the protein fibroblast growth factor 2 (FGF2) is active, it contributes to glioma stem cell self-renewal and tumor growth. However, researchers lacked understanding of how this process occurs.

For this reason, Lathia and colleagues sought to identify how glioblastoma cancer stem cells maintain their stemness. The researchers found FGF2 is a key intermediary in the multistep, pro-cancer signaling loop, and that “turning off” FGF2 potentially could prevent glioblastoma progression.

Healio spoke with Lathia about what led to this research, what he and colleagues found and what subsequent research will entail.

Question: What prompted this research?

Answer: For a long time, the field has known of a cancer stem cell population in advanced cancers, including glioblastoma. We have always wondered if there are communication mechanisms or ways that cancer stem cells can interact with their surrounding microenvironment for their benefit. We felt an unresolved question existed in the field about how cancer stem cells access additional nutrients in the microenvironment. We know from normal brain development that a lot of key growth factors are embedded in the matrix that surrounds the cells, but how the cells can gain access to the trapped growth factors remained unknown.

Q: How did you conduct the study?

A: We used a lot of human-derived glioblastoma samples from resected tumors. Through molecular biology approaches, we altered levels of the enzyme that we were interested in, and we used a series of preclinical animal models. We used a clinical grade inhibitor against the growth factor pathway that interested us to confirm the relevance of what we observed.

Q: What did you find?

A: Cancer stem cells produce an enzyme, ADAMDEC1, that they shed, which liberates key growth factors for the benefit of the cancer stem cells. We identified the interaction between ADAMDEC1 and FGF2 as a novel drug target for glioblastoma. Therapeutically targeting this interaction may be key to interrupting this cancer-driving loop. With standard treatment, median survival for adults with glioblastoma is only between 11 months and 15 months, and recurrence is common. New therapies are greatly needed.

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Q: What are the clinical implications of the findings?

A: If we can harness this inhibitor, we may be able to leverage it into a clinical trial. This study also sheds light on other molecular targets that can be developed, which other investigator teams at Cleveland Clinic are studying.

Q: What will subsequent research entail?

A: We want to see if we can develop therapies and get them into clinic faster based on this information, whether that involves targeting the enzyme or the growth factor signaling pathway. We also realize that although the cancer stem cells can secrete ADAMDEC1 and liberate growth factors, those growth factors can also influence nontumor cells in the microenvironment, so it may change the inflammatory state of the tumor. These tumors tend to be skewed toward an anti-inflammatory, pro-tumorigenic state, and we think a lot of this is driven by the set of growth factors being processed. We are trying to better understand the additional communication outside of the cancer stem cell secreting a factor for its own benefit. We think that surrounding cells may be influenced, as well, and we are testing this hypothesis.

Q: Is there anything else that you would like to mention?

A: This study is being co-led by myself, as well as a group in Wales, so it is a multinational collaboration. – by Jennifer Southall

Reference:

Jimenez-Pascual A, et al. Cancer Discov. 2019;doi:10.1158/2159-8290.CD-18-1308.

For more information:

Justin Lathia, PhD, can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: lathiaj@ccf.org.

Disclosures: The study was funded in part by the Lisa Dean Moseley Foundation. Lathia reports no relevant financial disclosures.

 

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