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Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

6825694281_dfb79615d6_zIf you’re a regular reader of this blog, or follow cancer literature, you’ll have heard of a signaling pathway called Hedgehog that is activated in many cancers, including brain, skin and even bladder. It’s a cute name for cellular cascade that can kill when inappropriately activated.

Neurologist Yoon-Jae Cho, MD, treats children with brain tumors called medulloblastomas. He and postdoctoral fellow in his lab, Yujie Tang, PhD, published a study yesterday in Nature Medicine that could one day help some patients whose Hedgehog-driven tumors have become resistant to available therapies.

As Cho explained in an e-mail to me:

Medulloblastomas are the most common malignant brain tumors in children. They are comprised of various subgroups, including one with activation of a strong oncogenic signal called the Hedgehog pathway. Notably, the Hedgehog pathway is also activated in several other cancers including basal cell carcinoma, the most common cancer worldwide. Therefore, pharmaceutical companies and several research groups have developed drugs to target this pathway.

The most common of these drugs targets a downstream protein component of the pathway called Smoothened, including one currently marketed by Genentechcalled vismodegib (trade name Erivedge) and an investigational drug produced by Novartis called LDE225. Blocking the activity of Smoothened stops the chain reaction leading to division of the cancer cells. You can think of it (in simplified terms) as a line of dominoes standing on end, waiting for an eager finger to begin the chain reaction. Removing one domino (nixing Smoothened activity) can sometimes stop the rest of the row from falling and block the cancerous cell from dividing. But, as Cho explained:

Unfortunately, many cancers activate the Hedgehog pathway downstream of Smoothened and are inherently resistant to these therapies. Other cancers that are initially responsive to these drugs develop resistance through activation of downstream Hedgehog pathway components.

Cho and his colleagues have now described a new, novel way to interfere with the Hedgehog pathway. They’ve found that compounds that inhibit a protein called BRD4 can stop the growth of human Hedgehog-driven cancers – even when they’re resistant to drugs blocking Smoothened activity. This is particularly interesting because the BRD family of proteins recognizes and binds to particular chemical tags on chromatin that control whether (and when) a gene is made into a protein. It’s the first time such an epigenetic regulator has been implicated as a target in the Hedgehog pathway. Additionally, it’s a new avenue to explore for patients with Hedgehog-driven medulloblastomas – as many as half of whom will be resistant to Smoothened inhibition, according to a previous study co-authored by Cho and members of the International Cancer Genome Consortium’s Pediatric Brain Tumor Project. Cho concludes, “Our study offers a promising new treatment strategy for patients with Hedgehog-driven cancers that are resistant to the currently used Smoothened antagonists.”

Previously: New skin cancer target identified by Stanford researchers, Humble anti-fungal pill appears to have noble side-effect: treating skin cancer and Studies show new drug may treat and prevent basal cell carcinoma
Photo by Phillip Taylor

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