“The two of us have worked on the lung cancer problem side-by-side for the past 40-plus years.” But back then, “there were no tumor lines. There were, at most, one or two lines in the whole world.”
When patients with lung cancer started walking into the medical center, Minna said, “Let’s take all of these patients, get them biopsied, and we’ll start tumor lines.” And this was the work he set out to do with Gazdar, which has lasted to this day. The idea was initially met with skepticism back then, but today, “we have whole genome sequences of lung cancer.” During his years at the naval medical center, from 1975 through 1981, these tumor lines became the basis for most of the preclinical research that has gone on in the field of lung cancer.
The tumor lines are now used frequently by thousands of investigators around the world. It might have been a case of being in the right place at the right time, but “those lines had some of the first EGFR mutations that were known. The 10 or so lines that we collected turned out to be the pivotal resources that were used to prove that sensitivity to EGFR could be used in preclinical models to lead to targeted therapies.”
Given that more than 60% of non–small cell lung carcinomas overexpress EGFR proteins, it has become an important therapeutic target for the treatment of lung cancer tumors. Minna and his fellow researchers did not squirrel away the lung cancer tumor lines, though. Their objective was always to make the lines accessible to every researcher around the world in order to facilitate collaboration, corroboration, and sharing of resources.
“There was a very free give-and-take exchange that occurred. It wasn’t just me that set the tone for that. We always understood that the real enemy was not each other, but the disease.” Couple this with a desire to nurture research ideas through teaching younger researchers or fellows and you have a potent combination of objectives. These dual objectives, to freely share resources and to teach, are the most important things Minna believes that he has accomplished in his storied career. “I’ve been involved in the training of all these people who have gone into lung cancer translational research.” His list of collaborators, students, and fellows is a veritable “Who’s who?” in lung cancer research, many of whom consider Minna a mentor and a friend.
That extensive collaboration proved beneficial, especially when working with lung cancer tumor lines, which proved very hard to grow, said Minna. “It turns out that lung cancer cells would often float. The cells would be discarded when the media they were growing in was changed.”
Minna was familiar with the work of Gordon H. Sato, PhD, a cell biologist who first attained prominence for his discovery that polypeptide factors required for the culture of mammalian cells outside the body are also important regulators of differentiated cell functions.
“Sato had the idea that you could take and grow cells in completely defined media and add in growth factors. This was better than using serum. We started doing that with lung cancer, and it turned out that you could inhibit the growth of tumors early on.
“I had heard and discussed this idea with Gordon, so the first time an opportunity presented itself, we took some patient specimens out and put them in defined media. We tried several different combinations and all of sudden we saw things grow that we hadn’t seen before,” said Minna.
One benefit of being regarded among your peers as someone who shares discoveries and advances without regard for career advancement is that it can result in fortuitous conversations that can move research forward. Minna recalled the use of the Southern blot, a method implemented in molecular biology for detection of a specific DNA sequence in samples from lung cancer tumor lines and noted the amplification of the MYC gene. Further research resulted in the discovery of other MYC gene family members: N-MYC and L-MYC.
As these discoveries were made, Minna received a phone call from J. Michael Bishop, MD. Bishop is best known for his Nobel-winning work on retroviral oncogenes. Working with Harold E. Varmus, MD, in the 1980s, Bishop discovered the first human oncogene, c-Src. Bishop had been studying childhood lymphoblastoma and neuronal-like neuroblastoma, in particular, a gene that appeared to be amplified. Before Bishop could say anything further, Minna asked, “Any chance this is related to MYC?”
Minna said the silence on the other end of the phone was deafening. Bishop asked him, “How did you know that?”
“I’m looking at this blot in lung cancer, and there’s an amplified gene that exhibits those very same characteristics,” said Minna.
Looking back on the conversation, Minna said, “It was one of those things where suddenly you knew it had to be true. That kind of discovery results from the sharing of information and data, and that led to the eventual identification of that gene.”