Research at Cornell: Why is testicular cancer is so easy to treat with chemotherapy?

Advances in chemotherapy have become an important method of cancer treatment, but many cancers still have a poor prognosis and do not respond well to chemotherapy. One type of cancer which has shown astonishing levels of response to chemotherapy is testicular cancer: in 1970, only 5% of patients with highly advanced testicular germ cell tumors survived to the 5 year mark; this number increased to 74% by the early 2000’s, a survival rate which remains considerably higher than other advanced solid cancers. This improvement has been attributed to the sensitivity of testicular germ cell cancer cells to chemotherapy. The million-dollar question remains: why this treatment is so effective in testicular cancer, and not in other types of cancer?

Tim Pierpont, a graduate student in Robert Weiss’ lab at Cornell, believes that the answer may lie in the unique properties inherited from the cells that gave rise to the tumor. Most testicular cancers arise from the germ cells (the precursors to sperm, or an egg in females), and the few that arise from other parts of the organ (5%) have much poorer outcomes. The unique properties of the germ cells may thus explain why these tumor cells are much more sensitive to the effects of chemotherapy.

Tim is studying the mechanism of DNA damage response in these cancerous germ cells. Because germ cells are the cells that eventually give rise to an embryo, any DNA damage, or mistakes made during DNA damage repair, could be passed on to the next generation with devastating results. Germ cells are thus much more likely than other cells to die if DNA damage is detected. Chemotherapy drugs that work by causing DNA damage are thus extremely effective in eradicating testicular germ cell cancer cells.

Tim’s results will help explain why testicular cancer is so easy to attack with chemotherapy, and hopefully offer clues on how to make other tumors similarly sensitive to chemotherapy.

Many thanks to Tim Pierpont who sat down with me to talk about his research and elucidated many aspects of DNA damage!

Cancer stem cells

Image credit: http://www.verastem.com/research/

The latest buzzword (or, rather, words) in the cancer research world is “cancer stem cells”. These stem cells are thought to exist in tumours, and the theory goes that they are the reason that many cancers reoccur and medications fail. But what are these stem cells really, and how are they going to help us understand and fight cancer?

Stem cells are, by definition, cells that are capable of self-renewal (when they divide at least one of the two cells remains a stem cell), and are capable of transforming into other cell types. We have small reserves of stem cells in our body, for example in the bone marrow we have stem cells that produce blood, or in the muscle we have stem cells that form new muscle fibers when we exercise or damage our muscles.

In cancer, it has been proposed that a similar small reservoir of cancer stem cells exists within the tumour, and  these cells are not always capable of being targeted by chemotherapies. Thus, drugs may cause the tumour to shrink, but cancer stem cells may still remain and produce new tumor cells. Furthermore, if these stem cells which survive, pick up a new mutation that renders them immune to the chemotherapy, the tumour becomes chemotheraphy-resistant and continues to grow. Therefore, the answer does not only lie in finding drugs that can attack tumors and reduce their size, but in also finding a way to attack a potential source of the tumour: cancer stem cells. Similar to a video game, you don’t win by attacking the little guys, you win by attacking the big guy at the end of the game.

Because stem cells could be the key to unlocking the secrets of fighting cancer, extensive research is now going into understanding and fighting cancer stem cells. Researchers are beginning to further understand the mechanisms that allow  cancer stem cells to be resistant to chemotherapy. These resistant properties, which differ from normal cells, may even be used to develop targets for future drugs aimed at cancer stem cells.

Many thanks to Tim Pierpont for suggesting the topic of this blog post and providing additional information! For a short video on cancer stem cells made by the Canadian Stem Cell Foundation, visit this link.

Join us Thursday night for a Cancer Resource Center fundraiser at Cinemapolis!

Cancer biomarkers

Broadly defined, cancer biomarkers are biological markers that indicate the presence of a cancer, much like the tip of an iceberg.  If these markers can be identified early enough, a disaster of titanic proportions can be averted. Cancer biomarkers can also offer additional clues about specific properties of the tumour, helping in treatment decision-making.

Cancer biomarkers are used to diagnose cancer, such as a tumor mass that is visible on an x-ray. But more recently, new biomarkers have allowed for even earlier detection of cancer. Progress is being made in different imaging techniques that allow better detection of tumors: 3D mammography results in 40% more detection of cancer and a reduction of 15% in callbacks for “suspicious” mammograms. Blood tests for high levels of prostate specific antigen (PSA) can indicate prostate cancer without ever looking at the prostate itself.

More recently, biomarker tests have been developed to test for a variety of genetic mutations that can make it very likely to develop cancer. The human genome was fully mapped in 2003, and now that we know what the different genes do, the next step is understanding what mutations in these genes can do. One high-profile example is the expression of the breast cancer, early onset (BRCA) gene, which has led some women (most famously Angelina Jolie) to have their breast or ovaries removed, rather than run the risk of potentially developing cancer.

The detection of cancer using early biomarkers has been controversial. Biomarker detection may lead to unnecessary treatment in patients who would have remained asymptomatic for the rest of their lives. On the flip side, these tests can provide a false sense of security in patients who unknowingly have cancer but do not have high levels of biomarker expression. In fact, some organization are now cautioning against PSA screening.

We are increasingly discovering that tumor formation relies on a variety of factors, with no two cancers being alike. Knowing this, detection of specific biomarkers is immensely promising for developing treatments tailored to the specific properties of the tumor, leading to more effective treatment.

Take for instance the protein HER2 that is present on the surface of cells, and is responsible for cell proliferation.This protein is often overexpressed in breast cancer, and leads to increased cell division-- a hallmark of cancer. Because it is expressed at the surface of cells, it is easily accessible, and drugs such as Herceptin have been developed to inactivate HER2 in cancer patients. Testing patients for this disregulation in HER2 leads to effective personalized therapies.

Other biomarkers can indicate whether specific drugs will be ineffective. Similarly to Herceptin, Cetuximab is used to block the EGF receptor, which acts on KRAS and BRAF. However, certain tumors (30-50%) bypass the EGF receptor and have mutations in KRAS directly, rendering Cetuximab completely ineffective! Patients are now tested for KRAS mutations, and drugs have been developed that target KRAS directly.

Further developments in this field will allow us to identify more specific biomarkers, detect cancer earlier with higher fidelity, increase the personalization of medicine, and offer patients better treatment.

Many thanks to Clint Stalnecker, who presented a seminar on cancer biomarkers for the Cancer Resource Center, which you can dowload here.