hypoxia Archives - Sanford Burnham Prebys

Tag: hypoxia

Institute News

To treat breast cancer, give it a lifeline

AuthorJessica Moore
Date

October 17, 2016

Stabilizing tumor blood vessels (red) would eliminate adaptation to low oxygen (green and blue)

In honor of Breast Cancer Awareness Month, we’re highlighting the work our scientists are doing towards the next generation of breast cancer therapies.

Providing more oxygen to a tumor might seem like exactly the wrong way to treat cancer. But Masanobu Komatsu, PhD, associate professor in the Cardiovascular Metabolism Program and the NCI-designated Cancer Center, is trying to find treatments that do exactly that. Enhancing a tumor’s blood supply, which carries oxygen to cancer cells, actually lowers the chance that the cancer will spread.

“We’re aiming to minimize one of the most challenging and devastating aspects of breast cancer—metastasis,” said Komatsu. ”Mortality rates for metastatic breast cancers are still incredibly high. Of the patients with cancer that has spread and led to tumors in other organs, almost 80% will survive less than five years.”

Cancer cells become more likely to move into other tissues as they adapt to a low-oxygen environment due to the tumor’s defective vasculature. Because these blood vessels grow abnormally fast, they form improperly—oxygen and nutrients leak out before reaching the tumor’s interior. However, the cancer cells buried within continue to divide and mutate, so some can survive the lack of oxygen. The master switch that enables cancer cells to generate energy by alternate means also triggers changes that let them enter the circulation and find new homes.

Strengthening the blood supply could also help make the cancer more vulnerable to therapeutic attack, Komatsu added. “Improving the circulation inside a tumor would help anticancer drugs—and the body’s own T cells, which also help eliminate cancer—reach all the tumor cells, and increasing oxygen levels helps sensitize them to radiation and immunotherapy.”

Animal studies suggest that normalizing tumor blood vessels confers such benefits, but existing drugs known to stabilize the vasculature have shown limited benefit. Komatsu and his lab are looking for better therapies by screening microRNAs, small pieces of genetic material that regulate gene activity.

With funding from the Florida Breast Cancer Foundation, the scientific team is testing each of hundreds of microRNAs to look for those that affect signaling pathways controlling the stability of tumor blood vessels. The microRNAs that come up positive could either be developed as drugs (to be used in combination with other cancer-killing treatments), or studied further to find new drug targets.

“This strategy is relevant not only to breast cancer, but to any solid tumor,” commented Komatsu. “The therapies we hope to find could help a huge number of patients.”

Institute News

Unveiling a tumor survival strategy points to new drug target

AuthorJessica Moore
Date

June 20, 2016

smear of squamous cell carcinoma

One of the reasons tumors can grow out of control is that they survive harsh conditions that normal cells can’t. For example, many can thrive even when supplies of oxygen are low, which happens when tumor growth outpaces the formation of oxygen-supplying blood vessels. Garth Powis, D.Phil., professor and director of SBP’s NCI-designated Cancer Center, has been studying how tumors adapt to this condition, called hypoxia, in hopes of finding ways to block it, which would kill certain cancers.

Surviving hypoxia requires a protein called hypoxia inducible factor-1 (HIF-1), which controls genes involved in switching tumor metabolism to oxygen-independent pathways and promotes the growth of new blood vessels. Though blocking HIF-1 would kill hypoxic tumors, finding drugs that achieve this has so far proven difficult.

A new study from the Powis lab published in Cancer Research may have found another way to overcome cancers’ hypoxia resistance.

The research team found that eliminating or blocking an enzyme called aldolase A lowers activity of HIF-1 and inhibits growth of breast cancer tumors in mice. Aldolase A is responsible for one of the steps in glycolysis, a metabolic process crucial for tumor survival, as cancer cells use it to generate energy more than normal cells.

“Our findings suggest that HIF-1 and glycolysis are a self-perpetuating cycle,” commented Petrus R. de Jong, MD, PhD, postdoctoral associate in Powis’ lab and co-lead author of the study.

“Turning off aldolase A breaks the cycle, decreasing both glycolysis and HIF-1 activity,” Geoffrey Grandjean, PhD, co-first author, explained. “This treatment strategy is a double whammy— it keeps tumors from generating energy without oxygen and it keeps them from becoming better vascularized to get more oxygen.”

To show that aldolase A can be blocked by a drug, Powis teamed with medicinal chemists at the University of Texas at Austin led by Kevin Dalby, PhD, professor of chemical biology, to develop an inhibitor, which slowed proliferation in cultured cancer cells

“The inhibitor we used hasn’t been optimized for use as an anticancer drug,” de Jong said. “However, it could inform future drug design— aldolase A is a very promising target.”

The paper is available online here.