A Protein that Can Melt Tumors Discovered

For the second time, cancer researchers at Vanderbilt have discovered a protein that—when genetically manipulated to impede it from interacting with a gene responsible for cancer genesis—effectively melts tumors in days. 

William Tansey, professor of cell and developmental biology, is dedicated to understanding how the oncogene MYC, an  highly conserved, noodle-like protein, works. It performs important functions in normal human development, and it often becomes reactivated in the deadliest and most difficult to treat cancers. 

Conducted experiment shows six tumor sizes grow for 15 days, at which point the MYC–HCF1 interaction is broken. After day 15, the tumors shrink and are gone. Cancer cells are dead by four days. 

MYC becomes the nitro in the tank, driving relentless rounds of cell duplication and division,” Tansey said. “The faster the cells grow and divide, they accumulate mutations, which give rise to cancer growth.” 

MYC has been an elusive drug target for at least 30 years, Tansey says, and has been considered “undruggable” because of its lack of structure. To work around this roadblock, Tansey set out to identify MYC’s more structured partner proteins with the goal of engineering mutations that disrupt the partners’ interactions with MYC that cause cancer growth. “If we can validate the physical contact between MYC and a protein, we can go after it therapeutically,” Tansey explained.  

Tansey and his collaborators have identified the protein Host Cell Factor-1 (HCF1) as a definite candidate for this type of therapeutic development. HCF1 is touched by MYC and is important for stimulating protein synthesis. When a cancer cell with MYC is genetically engineered to no longer interact with HCF1, the cancer cell begins to self-destruct. Developing a therapy that limits this interaction is a hugely promising step in cancer treatment 

The article, “MYC regulates ribosome biogenesis and mitochondrial gene expression programs through interaction with Host Cell Factor-1,” was published in the journal eLIFE on Jan. 8. 

Source: https://news.vanderbilt.edu/

A Weapon To Fight Lung Cancer

Researchers at the Children’s Medical Center Research Institute at UT Southwestern (CRI) have discovered a new metabolic vulnerability in small cell lung cancer (SCLC) that can be targeted by existing drug therapies.

SCLC is a deadly and aggressive form of lung cancer with few therapeutic options and an incredibly low five-year survival rate of 5 percent. Researchers at CRI believe the key to finding new therapies for this disease lies in better understanding the metabolism of SCLC.

Cancerous cells reprogram their metabolic pathways to grow and spread rapidly through the body. In some forms of cancer, cancer cells become highly dependent or “addicted” to specific metabolic pathways as a result of genetic mutations. Identifying these pathways can lead to new treatment options.

SCLC metabolism has not previously been studied in-depth,” said Dr. Ralph DeBerardinis, Professor at CRI and Director of CRI’s Genetic and Metabolic Disease Program.If we identify the metabolic pathways SCLC uses to grow and spread, then maybe we can find drugs to inhibit them. This could effectively cut off the fuel supply to these tumors.”

To discover new vulnerabilities in SCLC, researchers at CRI analyzed metabolism and gene expression in cells obtained from more than 25 human SCLC tumors. From the data, they identified two distinct categories of SCLC defined by the level of two oncogenes: MYC and ASCL1. Oncogenes are genes known to promote cancer formation and growth.

The study, published in Cell Metabolism, found that MYC stimulated synthesis of purine molecules. Purines are essential for cells to produce RNA and DNA, both of which are required for growth and division. MYC-expressing cells had a particular need for a specific type of purine called guanosine.

We were excited to discover that purine synthesis was so important for this subset of SCLC cells. There are already safe and effective inhibitors of guanosine synthesis used in patients for other diseases besides cancer. Our findings suggested that mice with MYC-expressing SCLC might benefit from treatment with drugs that inhibit purine synthesis,” said Dr. Fang Huang, a visiting scholar at CRI and first author on the paper.

To test the hypothesis, researchers treated mice from multiple different mouse models of SCLC with the drug mizoribine, a purine synthesis inhibitor. Treatment with this drug suppressed tumor growth and significantly extended the lifespan in mice with MYC-expressing SCLC.

Our findings suggest purine synthesis inhibitors could be effective in SCLC patients whose tumors have high levels of MYC. If we are right, this could quickly provide a new treatment for this disease, which has few options at present,” said Dr. DeBerardinis.

Source: https://www.utsouthwestern.edu/