Axel H. Schönthal Associate Professor Molecular Microbiology & Immunology, Molecular Pharmacology & Toxicology Keck School of Medicine School of Pharmacy

Education:
MS 1984 Biology - University of Karlsruhe, Germany
PhD 1988 Cancer Biology - University of Karlsruhe, Germany

Postdoctoral Research Fellowship:
1988 - 1991 University of California San Diego (UCSD)

Started at USC: 1992

Research Topics: Cancer Cell Biology, Cell Cycle, Growth & Proliferation, Cell Death, Signal Transduction, Drug Design, Delivery

Research Description

In general terms, our research is placed in the areas of molecular cancer biology and anticancer drug development. We are pursuing cross-disciplinary approaches to understand the mechanisms that determine tumor growth and chemoresistance. My lab closely collaborates with four other USC laboratories and our common determination and goal is to find a cure for cancer.

Students who are interested in joining my lab and participating in our "war on cancer" need neither guns nor bulletproof vests; rather, the minimum requirements are lab-coats and latex gloves - and serious commitment to academic excellence.

Cancer Models and Anticancer Agents

Our research uses three tumor types as models, namely breast cancer, multiple myeloma and brain cancer (glioblastoma), and involves a great variety of molecular, cellular, and pharmacologic procedures in vitro. We also pursue in vivo studies in mouse tumor models (although students who prefer to not work with animals may be exempt from such studies).

Most recently, we have focused on four different types of compounds that have shown promise as anticancer drugs:

1. HIV protease inhibitors (such as nelfinavir, saquinavir and ritonavir) that are currently prescribed to HIV-positive individuals with AIDS.
2. Proteasome inhibitors (such as bortezomib) that are already approved by the FDA for the treatment of patients with multiple myeloma.
3. Components of green tea (such as epigallocatechin-gallate, EGCG) that might have anticancer properties.
4. Newly designed compounds that are based on the pain killer celecoxib (more commonly known as Celebrex).

(For some basic information on the above agents, try Wikipedia.com).

Recent Discoveries

We have discovered that certain combinations of the above drugs are quite effective at killing different types of tumor cells. At the molecular level, we found that these anticancer drug combinations appear to work via mechanisms that are different from those that were originally ascribed to these drugs. For example, celecoxib was developed as a selective inhibitor of an enzyme called cyclooxygenase-2 (COX-2), and this is the basis for its function as a painkiller. However, we have discovered that the inhibition of COX-2 is not involved in the anticancer effects of this drug; rather, celecoxib inhibits tumor growth via the blockage of a calcium pump (called SERCA) that is located in the endoplasmic reticulum. We are now taking advantage of this discovery by designing and synthesizing new compounds that even more effectively target SERCA, which may lead us to even better anticancer drugs. One such compound is 2,5-dimethyl-celecoxib (DMC), and we have published a handful of papers describing its anticancer effects. Several other newly designed compounds are currently being investigated.

Not all drug combinations have turned out to be beneficial. For example, we have discovered that the combination of green tea (in particular, its major component EGCG) with the chemodrug bortezomib resulted in the complete blockage of therapeutic anticancer effects. We investigated this issue by molecular, cellular, pharmacologic, and chemical approaches and established the cause of this severe antagonism, i.e., we found that the EGCG molecule and the bortezomib molecule interacted with each other and formed adducts. As a result, the two agents were unable to attack tumor cells. This particular project has been a nice example where our findings were immediately relevant to clinical practice; in this case, our work led to the recommendation that cancer patients undergoing chemotherapy with bortezomib have to abstain from consuming green tea and green tea products.

Multidisciplinary and Interdisciplinary Approaches

In order to attack the cancer problem from various fronts, we have assembled a multidisciplinary battle group consisting of five laboratories that have been collaborating closely and successfully. The other four labs are those of Dr. Hofman (Department of Pathology), Dr. Chen (Department of Neurosurgery), Dr. Louie (Department of Pharmacy), and Dr. Petasis (Department of Chemistry). Below is a very brief description of each lab's contribution to our ongoing efforts.

(1) Work in the Schonthal lab is primarily focused on the molecular and cellular analysis of tumor cell growth and drug action. This involves various aspects of cell cycle regulation, signal transduction pathways, and apoptotic mechanisms taking place in drug-treated tumor cells in vitro and in animal tumor models in vivo. For this purpose, we are growing different types of tumor cells in culture dishes in an incubator. As long as these cells are kept at 37 degrees Celsius (= body temperature) and fed with the necessary amino acids and sugars, they multiply indefinitely. In this context, it may be interesting to contemplate the following: these cells were derived from tumors a long time ago; while the respective patients are (unfortunately) long dead and gone, their cells have lived on and are helping us in our battles against cancer!

(2) Dr. Hofman's lab works on tumor angiogenesis (new blood vessel formation), and our common goal is to determine how we can attack the blood supply of tumors most effectively with our drug combinations in order to "suffocate" the tumor tissue.

(3) Dr. Chen is a neurosurgeon who operates on patients with brain cancers; therefore, he has access to primary tumor samples from patients, from which we want to isolate brain tumor stem cells. Such stem cells are the ones that enable the tumor to recur after surgery (because tumor stem cells often survive treatment of the patient with chemotherapy or radiation); therefore, it will be critical to find drug combinations that are particularly effective in cancer stem cells.

(4) Dr. Louie is a clinical pharmacologist at the School of Pharmacy. Together with his lab we investigate how to optimize the concentration of our drug combinations inside tumor tissues. This study includes the pharmacologic blockage of drug efflux proteins (which can pump certain compounds out of the cell and therefore render drugs ineffective). This is important because such pumps oftentimes are overly active in tumor cells. Drug resistance due to increased activity of efflux pumps is a problem in cancer stem cells and also in those tumors that recur in patients after prolonged chemotherapy.

(5) Dr. Petasis is an organic chemist with terrific expertise in drug design. Together, we are designing and evaluating novel bioactive molecules that could lead to the discovery of more effective anticancer drugs. In particular, his lab has been producing the above-mentioned novel analogs of celecoxib, which we are evaluating and developing as more effective anticancer therapies.

Together, this multidisciplinary approach has proven quite successful and has resulted in numerous publications and further promising leads. We stay optimistic that our research efforts will pave the way for improved cancer treatments in the not-to-distant future.