Dr. Yosef Yarden
Weizmann Institute of Science
My affair with ICRF started on December 1, 1988, right after returning to Israel and upon completion of my postdoctoral training in America. Almost 4 years earlier, I left the Weizmann Institute, for San Francisco, where I trained at Genentech Inc., at that time still a young biotech company. The laboratory that hosted me at Genentech had just discovered a new cancer-promoting gene, aka an oncogene, that they called human EGF Receptor 2 (better known today as HER2). In parallel, an MIT research team led by Robert Weinberg discovered the same gene and called it Neu, for neuroblastoma. One of my assignments while at Genentech was to join a team that attempted blocking HER2/Neu by generating an antibody that would specifically recognize the culprit of some human tumors.
We raised several such antibodies; two of them became anti-cancer drugs: Trastuzumab/HerceptinTM was approved 13 years later for treatment of advanced (metastasizing) breast cancer. It took 14 additional years to transform the second antibody into an anti-breast cancer drug, called pertuzumab.
Toward the end of 1986, we moved from the Bay Area to Brookline, Massachusetts, and I started working for Robert (Bob) Weinberg. My assignment was to crack the mechanism by which Neu, the name HER2 received in the East Coast, converts normal breast cells into cancerous cells. Essentially, we assumed that Neu/HER2 acts as a receptor that binds a hormone-like molecule, in analogy to the estrogen receptor, which binds a hormone, estrogen.
Two years after joining the MIT lab I felt that I had a clue where to find the putative molecule. In parallel I broke a deal with my alma mater, the Weizmann Institute, to become an assistant professor. Mrs. Nurit Guter, who headed the Weizmann’s Grant Office, advised me to apply for a grant from ICRF. While still packing my belongings at MIT, I prepared the application under the title “Studies of the hypothetical ligand of the Neu oncoprotein”. I requested from ICRF 20,000 USD per year, for three years, although it took us almost 5 years to find the elusive molecule. This was my first ever grant and I am deeply thankful to the ICRF.
Twenty-six years later, and after receiving larger and longer research grants from the US Department of Defense, as well as from the National Cancer Institute (a Merit Award), ICRF has remained my first choice for especially original grants that help us follow serendipitous observations.
Let me end by a recent example. In an effort to understand why some breast cancer cells leave the gland and break into blood and lymph vessels to colonize distant organs, such as brain and bone,
we noted that this sequel of events can be instigated by exposing cells to a growth factor, called EGF. However, in the laboratory a steroid hormone, called cortisol, can abruptly stop this sequel. Cortisol plays a role in maintaining the body’s energy levels during the day. It is often referred to as the ‘stress hormone’ because its levels rise in stressful situations, rapidly bringing the body to a state of full alert. Since the steroid levels peak during waking hours and drop off during sleep, we asked how this might affect the HER2/Neu family of proteins, which as you might remember, promote cancer. With support from ICRF we came to an unexpected model: when cortisol levels are high, during the day, the HER2/Neu family and consequently tumor growth and metastasis, are strongly suppressed. Conversely, when we sleep and cortisol levels plunge, HER2/Neu and similar cancer-assisting machineries are freely running.
How relevant are these findings for cancers? To find out, we gave Lapatinib, one of the new generation of cancer drugs used to treat breast cancer, to mice with cancer at different times of the day and night. This drug is designed to inhibit HER2/Neu, and thus to prevent the growth and migration of the cancer cells. The results revealed significant differences between the sizes of tumors in the different groups of mice, depending on whether they had been given the drug during sleep or waking hours. Thus, it might be the rise and fall in the levels of cortisol over the course of 24 hours that hinder or enable the growth of the cancer. Further, administering certain anticancer drugs at night could be more efficient for therapy treatment.