Surprise small-cell lung cancer discovery suggests new treatment

Date:
February 24, 2022
Source:
University of Virginia Health System
Summary:
Scientists say the unexpected discovery about small-cell lung
cancer could lead to new treatment approaches for that cancer and
other forms of cancer as well.



FULL STORY ==========================================================================
An unexpected discovery at UVA Cancer Center has allowed scientists
to halt the development of small-cell lung cancer in lab mice, and
the surprise finding could open the door to a new treatment approach
in people.


==========================================================================
The researchers, led by UVA's Kwon-Sik Park, PhD, and John H. Bushweller,
PhD, were seeking to understand the role of a mutation in the EP300 gene
in the formation of small-cell lung cancer tumors. Their experiments
revealed that the gene makes a protein with surprising properties that
can both foster or prevent the development of small-cell lung cancer. By preventing the gene from acting as a tumor-promoter, the researchers
were able to stop the cancer from forming and spreading. This held true
in both cell samples and lab mice.

The protein's essential role in tumor formation makes it an enticing
target for researchers seeking to development new treatments for
small-cell lung cancer (SCLC), an exceptionally dangerous form of
cancer. Overall five-year survival for patients diagnosed with SCLC is
only about 7%.

"The most remarkable aspect of our findings is that we explained the
unique vulnerability of EP300 at the molecular level, down to a single
amino acid," said Park, of the University of Virginia School of Medicine's Department of Microbiology, Immunology and Cancer Biology. "Given
the frequent EP300 mutations found in a wide range of cancer types,
I hope that the concept of targeting the EP300 KIX domain will have
a more general applicability for cancer therapy." About Small-Cell
Lung Cancer Small-cell lung cancer is responsible for approximately 13%
of lung cancer diagnoses. Patients typically have better outcomes when
it is caught early, before it has spread outside the lung, but it is
a fast-growing cancer and is often discovered after it has already
spread. Smoking is a major risk factor.

Current treatment options include surgery, chemotherapy, radiation
and immunotherapy, but, for most patients, treatments do not cure the
cancer. That means better options are urgently needed.



========================================================================== UVA's new findings point to a potential new approach. Park and his
team made their surprise discovery while investigating the role of
the EP300 gene in the development of SCLC using genetically engineered
mouse models. Remarkably, they found the protein the gene makes could
both promote and suppress tumor formation. One component, or "domain,"
of the protein appeared to foster cancer development, while another
appeared to impede it.

The scientists further investigated the tumor-promoting domain, called
KIX, and found it was essential for SCLC development. The cancer couldn't
exist without it. The cancer, it turned out, had to get its KIX.

That suggests that targeting KIX could offer a way to treat SCLC in
patients, the scientists say. In a new scientific paper outlining
their findings, they call KIX a "unique vulnerability" in small-cell
lung cancer.

To explore this newfound vulnerability, Park immediately turned to UVA's Bushweller and Tim Bender, PhD, who previously had considered targeting
the KIX domain. A fruitful collaboration instantly ensued.

"Based on this data, we are quite excited to pursue the development
of a drug targeting the KIX domain, as this will likely have multiple applications for cancer treatment, particularly for SCLC and leukemia,"
said Bushweller, of UVA's Department of Molecular Physiology and
Biological Physics.

The researchers were pleased that their collaboration has produced such
a promising lead in the effort to develop better therapies for small-cell
lung cancer.

"This study was one of the best examples for the interdisciplinary collaborations happening at UVA, spearheaded by talented and hardworking postdocs Kee-Beom Kim and Asish Kabra," Park noted.

Shedding light on the causes of cancer and pioneering better ways to
treat it are urgent missions of the UVA Cancer Center, which on Feb. 1
became one of only 52 cancer centers in the country to be designated
as a Comprehensive Cancer Center by the National Cancer Institute
(NCI). The designation recognizes elite cancer centers with the most outstanding cancer programs in the nation. Comprehensive Cancer Centers
must meet rigorous standards for innovative research and leading-edge
clinical trials.

The work was funded by the National Institutes of Health, grants
R01CA194461, U01CA224293, R01GM100776, R56AI108767, R01CA204020,
P30CA044579 and P30CA008748; a UVA "Three Cavaliers" grant; and an
Adenoid Cystic Carcinoma Research Foundation grant.

========================================================================== Story Source: Materials provided by
University_of_Virginia_Health_System. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Kee-Beom Kim, Ashish Kabra, Dong-Wook Kim, Yongming Xue, Yuanjian
Huang,
Pei-Chi Hou, Yunpeng Zhou, Leilani J. Miranda, Jae-Il Park, Xiaobing
Shi, Timothy P. Bender, John H. Bushweller, Kwon-Sik Park. KIX
domain determines a selective tumor-promoting role for EP300 and
its vulnerability in small cell lung cancer. Science Advances,
2022; 8 (7) DOI: 10.1126/sciadv.abl4618 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220224091119.htm

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