Cancer 101 One persons view.... Andrew Thorburn

Some things to bear in mind about Cancer Second leading cause of death in the western world. Rapidly becoming more and more important cause of death in developing world. Cancer rates are rising (primarily caused by increasing life span) although mortality is decreasing. Compared with progress for other major killers-e.g. cardiovascular disease, progress against cancer has been dismal. However, we have seen significant improvements in survival for some tumor types (e.g. testicular cancer, children’s leukemias, some breast cancers), little progress for others (e.g. glioblastoma, lung cancer, pancreatic cancer).

Development of Cancer cell growth = cell death Activate oncogenes Inactivate tumor suppressors cell growth > cell death cell death < cell growth

Most Human Cancers probably take decades to develop Suppose we were able to delay the whole process by just 2-3 fold? B Vogelstein et al. Science 2013;339:1546-1558

How to deal with Cancer... Prevent as much cancer as possible (probably about half of cancer mortality can be prevented just with things we already know about). Detect it early when its easier to deal with (but be clever enough to ignore cancers that we really shouldn’t be trying to treat). Effectively treat the rest - ideally using personalized treatments that have limited toxicities and side effects. After you’ve had cancer get the optimal support and care to ensure that CA survivorship is a good experience

Cancers often have lots of mutations Cancers often have lots of mutations.... and different ones add on new (often bad) behaviors to the tumor cells Genetic alterations and the progression of colorectal cancer. The major signaling pathways that drive tumorigenesis are shown at the transitions between each tumor stage. One of several driver genes that encode components of these pathways can be altered in any individual tumor. Patient age indicates the time intervals during which the driver genes are usually mutated. Note that this model may not apply to all tumor types. TGF-β, transforming growth factor–β. Published by AAAS B Vogelstein et al. Science 2013;339:1546-1558

Cancers often have lots of mutations.... But the important ones that drive tumor growth seem to be in about a dozen signaling pathways that control cell fate, cell survival & growth and maintenance of the genome. Some tumor types have more of these “drivers” than others Number of somatic mutations in representative human cancers, detected by genome-wide sequencing studies. (A) The genomes of a diverse group of adult (right) and pediatric (left) cancers have been analyzed. Numbers in parentheses indicate the median number of nonsynonymous mutations per tumor. (B) The median number of nonsynonymous mutations per tumor in a variety of tumor types. Horizontal bars indicate the 25 and 75% quartiles. MSI, microsatellite instability; SCLC, small cell lung cancers; NSCLC, non–small cell lung cancers; ESCC, esophageal squamous cell carcinomas; MSS, microsatellite stable; EAC, esophageal adenocarcinomas. The published data on which this figure is based are provided in table S1C. Published by AAAS B Vogelstein et al. Science 2013;339:1546-1558

Hallmarks of Cancer

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Prevention Strategies Change behaviors that we know lead to cancer: tobacco, obesity, diet, exercise, sun exposure, nasty chemicals etc. Are there other important prevention strategies still out there waiting to be found or is it just a matter doing what we know we should do already?

Detection Strategies New technologies may allow us to detect cancer at its earliest stages--can we do for other tumors what we can do for colon cancer where early detection can allow us to find and destroy tumors before they are bad? Could there be a regular, reliable blood test to tell you if you’ve got tumor cells lurking in your body? But how do we discriminate between the bad cancers and the ones we can safely ignore--will prostate CA where we may often actually over-treat people be the model?

Treatment What do we do if prevention didn’t work and early detection didn’t catch it before it was a real tumor?

A short (and incomplete) history of cancer treatment... ~1600 BCE--Egypt. Try to treat breast cancer by cauterization using “fire drill”--conclusion ”there is no treatment” ~400 BCE--Greece. Hippocrates- no effective treatment, better to not try to treat cancer. ~200 CE--Rome. Galen cancer caused by “unbalanced humors”--patient incurable, except in rare cases of breast cancer where the complete tumor was removed mid 18th Century. John Hunter-”father of scientific surgery”--surgery can cure cancer if you remove all the tumor.

early 1900s. Use X-rays/radiation to kill cancer cells. 1940s. Louis Goodman & Alfred Gilman: use nitrogen mustard to treat lymphoma. Sidney Farber--kill cancer cells with chemotherapy that blocks essential processes in a cell. 1960s-1980s. Combine chemotherapy; significant progress with some tumors (e.g. pediatric ALL, testicular cancer). late 1990s. Improved use of radiation and traditional chemotherapy. Targeted therapy-go after the defects in the tumor cells rather than just treating with toxic agents that kill all cells (normal and tumor). 2000- Hundreds of new agents, most try to selectively target tumor cells and avoid killing normal cells but usually work for only some people.

Kamb et al. Nature Reviews Drug Discovery 6, 115–120 (February 2007) New cancer drugs have lower success rates than drugs to treat other diseases Success defined as: % of drugs tested in humans that were approved for use by the FDA 95% of oncology drugs that are tested in people fail, this doesn’t count the ones that don’t even get into people! Kamb et al. Nature Reviews Drug Discovery 6, 115–120 (February 2007)

Targeting the Hallmarks

If you get a drug that works, the results can be spectacular

For most tumors, when drugs do work, they only work for some people....

The good news: Ross Camidge August 2007 (peak response) Oct 2006 (baseline) August 2007 (peak response) Ross Camidge

The bad news: it stopped working August 2007 (peak response) Jan 2008 (regrowth pelvic lesion)

...but not in all the tumors August 2007 (peak response in pelvis) Jan 2008 (continuing response in other lesions)

The way we hope cancer therapy is going...

Targeting the Hallmarks 23

Epidermal Growth Factor Receptor as an example of a therapeutic target

EGFR Signaling (greatly simplified) 12

how do we decide on the best target? EGFR Signaling (simplified a bit less) how do we decide on the best target?

Too many potential drug combinations to make sense of? Difficult to make sense of....But, a good problem for us to have!

Survivorship Will our treatments cause other problems? Including other cancers? How do we ensure that after cancer people live healthy (healthier!) happy lives?

Bottom Line Cancer is a hard problem – you’re really trying to kill off bits of yourself and fighting natural selection But it’s not hopeless. We know how to prevent at least half of it. It takes a long time for cancer to develop so there is usually plenty of time when one could step in and deal with the problem. We know cancer is a genetic problem but think there are a core set of relatively few pathways that are important– these are the targets that we are now going after. But we need to know who to treat and find ways to get around resistance. The only way to make real progress (after at least 3,500 years!) is by working together and dealing with every aspect of the problem.