Wednesday, June 11, 2014

Secret Science Club Post Lecture Recap: Targeting Tumors

Last night, I headed down to the beautiful Bell House in the Gowanus section of Brooklyn for this month's Secret Science Club lecture. Last night's lecture, a collaboration between the Secret Science Club and Lasker Foundation, featured Dr Charles Sawyers, whose C.V. is most prestigious... cutting and pasting from the SSC blog post, he's "chair of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center, investigator at the Howard Hughes Medical Institute, and professor in the Cell and Developmental Biology Program and Department of Medicine at the Weill Cornell Graduate School of Medical Sciences". Wow, the man is affiliated with some incredible institutions... poking around the t00bz, I also discovered that he is president of the American Association for Cancer Research.

The topic of the lecture was cancer treatment using "targeted" medicines. Dr Sawyers began the talk with a rueful mention of the inadequacy of funding for medical research. He followed this clarion call for better funding with a basic definition of cancer- cancer involves the development of tumors, which are abnormal growths of tissue. A benign tumor is a non-invasive mass, while a malignant tumor "invades" surrounding tissue. Metastatic tumors have infiltrated numerous tissues throughout the body. Traditionally, tumors were treated using surgery, radiation, chemotherapy, or a combination of the three. Dr Sawyers stated that a new approach was needed to treat cancer, a targeted approach.

Cancer is caused by mutations in the host's DNA- these mutations can be inherited or due to environmental conditions (such as carcinogens present in tobacco smoke or overexposure to the sun's UV rays). Oncogenes are genes which can potentially result in cancer, while suppressive genes act against tumor formation. Proto-oncogenes are involved in normal development, but can mutate to form an oncogene, which will result in cancerous growth. Suppressive genes stop cell growth, but can malfunction- a lack of suppressors will cause tumor growth.

As an example of the role of genes in cancer, Dr Sawyers cited the example of chronic myeloid leukemia, a blood cancer which causes an overproduction of white blood cells. Chronic myeloid leukemia involves a genetic transposition called the Philadelphia chromosome- researchers noticed that chromosome 22 in CML patients was stubby, while chromosome 9 was elongated- in the tumor cells there was a reciprocal translocation of genetic material between chromosome 22 and chromosome 9, shortening 22 and lengthening 9. The particular gene translocated is the Abl gene, which becomes fused with the BCR gene on the 22nd chromosome. The BCR-ABL fusion results in a kinase which binds ATP with a substrate, causing a chain reaction that results in abnormal growth. Dr Sawyer not only had a sweet animation of ATP engaging with the kinase, but had two models of the kinase that ended up on the bar by the end of the lecture (they were eventually returned to him, along with a nice IPA). A drug, marketed as Gleevec, was formulated to "jam" the active loop between the ATP and the kinase in order to stop abnormal white blood cell growth- the drug mimics ATP, but lacks the phosphate group that binds with the kinase, resulting in a reduced white blood cell count within thirty days.

Tumor cells can develop a resistance to drugs such as Gleevec, resulting in a relapse. A one nucleotide difference in a gene can prevent the ATP binding which stops the abnormal cell growth. The binding problem is solvable using new drugs that will work when the cancerous cells evolve resistance. There are over 500 kinases which bind ATP, and Gleevec can bind three of them- specific drugs are needed to bind specific kinases. As gene sequencing becomes more rapid, and less expensive, targeted therapy has improved, and implementation is more rapid. Since cancer is caused by mutation, efforts are underway to sequence the genetics of all cancers- new technology has reduced the cost of genetic sequencing to about $3,000, so tumors are now sequenced routinely. Once sequencing takes place, the DNA of cancerous cells is compared to that of healthy cells and "silent mutations" are filtered out. Once a database is created, the number of mutations in a tumor can be determined. There is a vast difference between the number of mutations in pediatric tumors, which can have a nucleotide "mistake" rate as low as one in a billion, and adult tumors, which average 50-100 mutations.

One ongoing project is determining where mutations occur, and compiling a "data map" of cancer genes. Currently, there are 140 "mapped" cancer genes, with 200 being the projected number of cancer genes. Out of the 140 known cancer genes, 60 are dominant and 80 are recessive. These genes regulate cell growth, cell fate and cell death (for example, malfunctions of the epidermal growth factor can result in unregulated cell division- Dr Sawyer illustrated this with an animation of out-of control cell growth among intestinal villi). In normal growth, undifferentiated stem cells can differentiate into progenitor cells, which can only differentiate further into a specific "final cell". In the course of the normal cell cycle, cell death eventually occurs.

In the case of cancers involving a malfunction of the Epithelial Growth Factor, the drug Erlotinib, another kinase inhibitor, was developed to block the growth signalling pathway. Targeted therapy has grown rapidly in the past decade and a half, with thirty-seven drugs being developed between 2001 and 2013. The therapeutic goal is to have three drugs per tumor gene, in order to counteract the development of drug resistance.

The key to developing targeted therapies is better cancer taxonomy. Put simply, knowledge makes treatment more successful. Dr Sawyer indicated that immunotherapy- harnessing the body's immune system to fight tumor cells, is a promising area of future inquiry.

In the Q&A session, some so-and-so asked the question that the Bastard was planning on asking, concerning the role of viruses in human cancers. Dr Sawyer implicated three viruses in cancers- the human papillomaviruses, Hepatitis B, and Hepatitis C. While formulating another question, the Bastard received a job-related phone call and had to go to his field office (the men's loo, natch) to answer the call.

Here is a video of Dr Sawyer giving a similar lecture on CML and targeted therapy (note the sweet ABL-BCR animation at around 3:15):

He looks kinda thirsty in that video... he didn't have that problem at the Bell House.

Once again, the Secret Science Club has delivered a top-notch lecture. In this case, the SSC and the Lasker Foundation were able to combine in a synergistic effect, powerful enough to overcome even the most resistant ignorance.
Special thanks to Dorian, Margaret, Dr Sawyer, and the staff of the beautiful Bell House... again!


ifthethunderdontgetya™³²®© said...

Put simply, knowledge makes treatment more successful.


Smut Clyde said...

IIRC, the Hep viruses are a factor in cancer because they keep irritating and damaging the liver. So liver cells keep multiplying to regenerate, and every cell division is a risk. Not an *interesting* effect like directly targetting oncogenes or anything.