Attacking tumors from the inside
Two experimental drugs fight non-small cell lung cancer by affecting
their blood vessels, oxygen levels, and other environmental factors

Date:
September 3, 2020
Source:
UT Southwestern Medical Center
Summary:
A new technology that allows researchers to peer inside malignant
tumors shows that two experimental drugs can normalize aberrant
blood vessels, oxygenation, and other aspects of the tumor
microenvironment in non-small cell lung cancer (NSCLC), helping
to suppress the tumor's growth and spread, researchers report.



FULL STORY ==========================================================================
A new technology that allows researchers to peer inside malignant tumors
shows that two experimental drugs can normalize aberrant blood vessels, oxygenation, and other aspects of the tumor microenvironment in non-small
cell lung cancer (NSCLC), helping to suppress the tumor's growth and
spread, UT Southwestern researchers report.


==========================================================================
The findings, published online in Cancer Research, highlight the use of
this novel visualization tool as well as the promise of these drugs for
NSCLC, a disease that remains one of the leading causes of cancer-related deaths in the U.S. despite decades of research.

NSCLC is the most common form of lung cancer, comprising about 85-90
percent of the nearly 230,000 cases of lung cancer diagnosed each year
in the U.S.

However, despite state-of-the-art treatments for this disease, including targeted therapies and immunotherapies, the five-year survival rate for
lung cancer remains at only 10-20 percent -- far lower than for many
other cancers including breast (90 percent) and prostate (99 percent.)
The experimental drugs cyclopamine tartrate (CycT) and heme-sequestering peptide 2 (HSP2) have shown promise in inhibiting cancer growth and
progression in mice bearing human NSCLC tumors. Although it's known that
both of the drugs target heme, the molecule that carries oxygen in red
blood cells -- CycT inhibits heme synthesis and HSP2 inhibits heme uptake
into cells -- how these therapies work to suppress NSCLC was unknown.

To answer that question, Li Liu, Ph.D., assistant professor of radiology
at UTSW, and her colleagues used a new tool called multispectral
optoacoustic tomography (MSOT) to examine the inside of human NSCLC
tumors growing in mice.

(The imaging technology uses light pulses to generate ultrasound
waves.) They looked specifically at tumor blood vessels and how well
they carried oxygen to the cells within, comparing tumors in animals
that received injections of either CycT, HSP2, or saline every three days.

After three weeks, tests showed that either drug significantly suppressed
the growth of the tumors compared with mice that received just saline, supporting previous studies. But Liu, a member of the Harold C. Simmons Comprehensive Cancer Center, and her colleagues showed that while
untreated tumors consumed copious amounts of oxygen, lowering this blood
gas in the tumor microenvironment, tumors in mice treated with CycT or
HSP2 consumed significantly less. Similarly, these animals generated
less ATP, a molecule that cells use for energy that requires heme for
its formation.



========================================================================== Using MSOT, they found that treatment with either drug reduced the
abnormally large amount of blood vessel formation in these tumors and
increased blood oxygen saturation and tumor oxygenation, bringing both
of these measures closer to that of healthy tissue. The treatments also
reduced the amount of total hemoglobin, a measure that reflects the
amount of blood circulating through tumor tissue.

Further experiments showed that cells isolated from the tumors of mice
treated with CycT and HSP2 had reduced amounts of molecular markers for
low oxygen and molecules associated with blood vessel formation.

Together, Liu says, these findings suggest that these two heme-targeting medications can attack NSCLC tumors from multiple angles: inhibiting the production of ATP and the oxygen consumption they need to live and grow, reducing blood circulation and oxygen levels to that of healthy tissue,
and decreasing the tumors' ability to create new blood vessels. This study
also shows the utility of MSOT as a noninvasive tool to survey tumors
and track how well drugs such as CycT and HSP2 are working in real time.

"The more we learn about these deadly tumors and potential new
treatments," says Liu, "the more hope we can offer patients, who currently
have few effective options for therapy." Clinical trials are underway at
other institutions to explore the feasibility of using MSOT to evaluate
tumors in patients, she added.

Other UTSW researchers who participated in this study were Yihang Guo,
Jingyu Chen, Shigen Zhong, James Campbell, Jeni Gerberich, and Ralph
P. Mason. Other contributors from local or international institutions or companies included Poorva Ghosh, Adnin Ashrafi, Sachareeka Dey, Jie Liu,
Purna Chaitanya Konduri, Li Zhang, and Massoud Garrossian.

This study was funded by Cancer Prevention and Research Institute of
Texas grants RP160617 and RP200021 and infrastructure provided by the Southwestern Small Animal Imaging Research Program (SW-SAIRP) supported
in part by P30 CA142543 and Shared Instrumentation Grants 1S10 RR024757,
S10 OD018094-01A1.


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


========================================================================== Journal Reference:
1. Poorva Ghosh, Yihang Guo, Adnin Ashrafi, Jingyu Chen, Sanchareeka
Dey,
Shigen Zhong, Jie Liu, James Campbell, Purna Chaitanya Konduri,
Jeni Gerberich, Massoud Garrossian, Ralph P. Mason, Li Zhang,
Li Liu. Oxygen- Enhanced Optoacoustic Tomography Reveals the
Effectiveness of Targeting Heme and Oxidative Phosphorylation at
Normalizing Tumor Vascular Oxygenation. Cancer Research, 2020; 80
(17): 3542 DOI: 10.1158/0008- 5472.CAN-19-3247 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200903114204.htm

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