(Arek Socha, Pixabay)
29 July 2022. A new biotechnology company demonstrated in lab mice its therapy for glioblastoma, an aggressive brain cancer, that overcomes limitations of current treatments. The founders of Modifi Biosciences in New Haven, Connecticut published their findings in yesterday’s issue of the journal Science (paid subscription required), with the company raising $6.4 million in seed funds.
Glioblastoma, also known as glioblastoma multiforme, is an aggressive brain cancer, making up about half of all malignant brain tumors in the U.S. The condition affects glial cells that support neurons, or signaling nerve cells in the brain. Glioblastoma is considered difficult to treat, usually with surgery or radiation to slow progression of the disease. According to National Brain Tumor Society, the average survival time for people with glioblastoma is eight months, with a five-year survival rate of about seven percent. Some 13,000 people in the U.S. are expected to be diagnosed with glioblastoma this year.
A drug approved to treat glioblastoma is temozolomide, an oral chemotherapy designed to kill cancer cells. As the Science paper points out, temozolomide contains a DNA methylation agent controlling gene expression, which at first slows tumor growth, but in as many as two-thirds of glioblastoma cases, patients develop a resistance to the drug. The researchers trace the resistance to a lack of a key repair protein known as O6-methylguanine methyl transferase or MGMT. This key repair protein is activated by a mechanism called the mismatch repair pathway, also missing in glioblastoma tumors.
A team from Yale University in New Haven developed chemical agents that seek to circumvent the DNA mutations in glioblastoma tumors responsible for resistance to temozolomide. The researchers, led by radiology professor Ranjit Bindra and chemistry professor Seth Herzon, designed their compound, code-named KL-50, to create a lesion in the tumor DNA that induces a separate mismatch repair pathway. By creating this alternative repair mechanism, KL-50 produces molecules toxic to tumor cells, but benign to healthy cells and tissue. In addition, the team designed KL-50 as an analog to temozolomide, taken as an oral drug.
Mutations that make the drug invisible
“A major problem in treating gliomas is that patients can rapidly develop resistance to the drug temozolomide, which has been the backbone of most glioma treatments for over 20 years,” says Bindra in a university statement. Herzon adds, “Resistance arises from acquired genetic mutations that essentially make the drug invisible after about a year, leading to recurrence and death in most cases.”
The researchers tested KL-50 in lab cultures and cell lines, and then in lab mice, first with brain tumor cells grafted to their limbs, and then induced with brain tumors. The results show in both tumor samples, mice receiving oral doses of KL-50 experienced shrinkage of their tumors under varying conditions of MGMT and mismatch repair pathway presence. Untreated mice, or those receiving temozolomide alone in most cases show little change in their tumors over time. Giving KL-50 to healthy mice also shows the animals tolerated the drug, except at the highest doses.
Bindra, Herzon, and co-lead author Kingson Lin founded a company first called Aztek Bio, now Modifi Biosciences, to license and further develop their technology for cancer therapies. Earlier this year, the enterprise began operating in a bioscience business center in New Haven, and yesterday announced the raising of $6.4 million in seed funds. Taking part in the financing are HighCape Capital, Connecticut Innovations, Ironwood Capital, the Brain Tumor Investment Fund, and Yale Ventures. One of the company’s founders is Kevin Rakin, a partner in HighCape Capital, a life science venture investor.
Modifi Bio, and the authors, believe KL-50 can lead to treatments for other cancers resulting from faulty DNA repairs. “Our discovery,” notes Bindra in a company statement released through Globe Newswire, “represents a major step forward in changing the treatment paradigm for this devastating disease, as well as for many other cancers with intrinsic DNA repair defects.”
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