"Collaborations, internal and external, are key to success at Genentech."
I came to Genentech in 1990 thinking I would be here only for a few years. I loved the work and the culture so much that I've been here ever since.
Over the years I have had many collaborations across the company. Recently, my lab's interest was mostly focused on the characterization of the hedgehog signaling pathway and the development of pathway antagonists for the treatment of various cancer. This project has evolved into a multidisciplinary project that involves many departments across the organization, which has given me the opportunity to interact with fantastic people.
The Hedgehog (Hh) pathway is a signaling cascade that directs patterning in most animals and is crucial for proper development. At the molecular level, Hh ligands drive cell proliferation in some cell types while causing others to undergo differentiation. Hh signaling is most active during embryogenesis and aberrant reactivation of the pathway in adult tissue can lead to the development of cancer.
Mutations in the Hh receptor components, Patched (PTCH1) or Smoothened (SMOH), result in constitutive pathway activation and have been identified in tumors such as basal cell carcinoma and medulloblastoma. The lab is interested in (i) understanding the contribution of Hh signaling in cancer by using genetic mouse models of cancer, (ii) uncovering signaling mechanisms by which the Hh signal is transduced into a cell and how novel therapeutic agents that target the Hedgehog pathway work for the treatment of cancer and finally (iii) understand the mechanism of resistance to hedgehog pathway inhibitors.
More recently my lab has become interested in the role of intestinal stem cells in homeostasis and in tumor development. While developing agents to target stem cells in the gut we have uncovered mechanism(s) of compensations that allows the GI track to tolerate depletion of the stem cell compartment during homeostasis but not under various challenge situations. However this mechanism probably also reflects a great deal of plasticity in tumors as well and we are studying the signaling mechanisms that underlie this phenomenon as well as various approaches to target stem cells in cancer.
Nature. 2017 Mar 29;543(7647):676-680.
We are studying and targeting a number of important developmental signaling pathways such as Wnt, Hedgehog and Notch. These signaling pathways play critical roles during embryogenesis in pretty much every organ of the body where they modulate proliferation or differentiation of numerous cell types. It is however becoming increasingly clear that these pathways are involved in tumorigenesis when reactivated in adult tissues through mutations or overexpression of pathway components.
This work has led to the development of vismodegib, a hedgehog pathway inhibitor, which targets Smoothened. Vismodegib was approved in 2012 by the FDA for the treatment of basal cell carcinoma (BCC), which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation We are also involved in a number of earlier stage initiatives using genetic mouse models of cancer to better predict drug efficacy, sequencing the genome of various tumor types to better understand how tumor develop and how to target them as well as as well as cancer and functional genome projects to identify novel drug targets in various therapeutic areas.
If DNA is a symphony, the science of epigenetics is the conductor making sure every cell plays its part.