Meditations of an oncology geek

Thought Experiment: How would you design a cancer drug?

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13 November 2011

I wrote on this topic a while ago, and figured it would be good to re-visit now that my readership has grown.

“Those who have not been trained in chemistry or medicine may not realize how difficult the problem of cancer treatment really is. It is almost- not quite, but almost- as hard as finding some agent that will dissolve away the left ear, and leave the right ear unharmed. So slight is the difference between a cancer cell and its normal ancestor. “
-William Woglom

The immune system is amazing. Immune cells systematically search out and destroy all invaders and diseased cells by constantly infiltrating tissues to determine friend from foe. Immune cells do so with such clarity that almost nothing escapes, despite many threats on a daily basis. Even organ transplants from a child to parent are rejected by the host immune system without the permanent use of heavy immuno-suppressant drugs.

Cancers evade the host immune system.

Cancer cells are so much like normal cells that the immune system cannot tell the difference. Now, imagine trying to make a drug that can infiltrate the entire body and even affect individual cancer cells lodged in tissues far away from the primary tumor. And here’s the kicker: how do you do it without killing everything else?

So I guess one would have to ask: How do cancer cells differ from normal cells, and of those differences, which ones can we exploit to kill cancer cells and not regular ones?

On a basic biological level, there are a few things that differentiate cancer cells from normal cells:
1) Cancer cells require more simple sugars than most tissues (known as the Warburg Effect )
2) Cancer cells often grow vey fast
3) Cancer cells have to migrate to activate biochemical pathways that allow them to spread
4) Cancer cells recruit new blood vessels

Note: This overview of advanced cancer treatment strategies is not exhaustive, but I chose to focus my discussion on these for the sake of clarity and brevity, and because these strategies are the ones most implemented in the clinic. I would love to talk about potential for selectively killing cancer cells through apoptosis but that would seem rather self-serving because of my own research focus. Anyway, I digress…

1) If healthy tissue is organized like New York City, tumor tissue is organized like the slums of Mumbai (see photos). Both house dense populations of people that eat, sleep, give birth, die, and produce human waste. New York is a model for efficiency in transportation, communication, and sanitation. Mumbai is the opposite. Like regular tissue, tumor tissue needs oxygen and has to get rid of CO2. Because of the haphazard organization of tumors, this process happens less efficiently, and as a result, tumors often rely on a less-efficient biochemical means to generate energy: glycolysis. Consequently, tumors like sugar. A lot. In fact, cancer patients are often told to avoid consuming lots of simple sugars (i.e. sweets) for this reason.

So, why not eliminate all sugar from your diet? Well, that’s not so easy. Any food we ingest is eventually broken down by the body into glucose (a simple sugar) and released slowly into the blood stream twenty-four hours a day. All tissues rely on at least some level of sugar to be in the blood stream, and cutting off all sugar would render you clinically dead. Not consuming large amounts of simple sugars means that the tumor will burn like an ember instead of a blaze.

2) As I mentioned in a previous article on why cancer patients lose their hair, traditional chemotherapeutics exploit the cellular machinery that allows cells to pull themselves apart into two halves during cell division. As a result, these therapies cause all cells in the body to be damaged when they divide, but since cancer cells (theoretically) divide very quickly, they are damaged more than other cells in the body. In a sense, traditional chemotherapeutics are not much more than glorified poisons. But, for decades they have been the best treatment option medicine has had.

As our knowledge of cancer biology defines the genes that go haywire, we start to see more specific ways to selectively affect cancer cells. I’ll give an example: twenty years ago, if you were diagnosed with Chronic Mylogenous Leukemia (CML), you had a 95% chance of being dead in twelve months. Now you would have approximately a 90% chance of survival. CML has a particular genetic kink in its armor – an oncogene forms from a mismatching of chromosomes that leads to a protein, which causes its uniquely fast growth rate. That protein exists only in CML cells and not in any other cells in the body, so scientists designed a drug to attack that protein and inhibit its cancer-promoting activity. The result was Imatinib, or Gleevec (its trade name). Compared to traditional chemotherapeutics, Gleevec has almost no side effects and is highly effective in treating CML.

Other types of cancer have similar dependence on oncogenic enzymes for their growth. I could go on for another couple articles about which drugs are currently in development and the cancers they target, and even in the next few years there will be several new tools for oncologists to use to treat cancer.

3) The most deadly aspect of cancer is its ability to spread through the body and invade new tissues. This process is called metastasis. Below is a three-dimensional animation of a PET scan from a cancer patient (source: University of Chicago Radiology PET-CT department). As mentioned above, cancer cells rely heavily on simple sugars, and a PET scan shows tissues that have high glycolytic activity. Now imagine being a surgeon tasked with removing all these tumors. Once cancer has begun to spread it is extremely hard to remove surgically.

However, not many cells in the body can migrate through tissues, and adults can tolerate blocking this biochemical pathway. There are drugs currently entering clinical trials that target this particular vulnerability. Early indications are that these new classes of drugs are well tolerated, though I cannot divulge more because of my proximity to some of these studies.

4) Growing tumors recruit new blood vessels: they cause existing blood vessels to branch out and grow towards them, feeding tumors with oxygen and nutrients (albeit in a haphazard manner, see above). This process is called angiogenesis and it employs a unique biochemical pathway (sound familiar?).

In adults, there are only two instances where angiogenesis occurs: traumatic wound healing (tissue regeneration) and menstruation. Neither process is vital for survival, unless you are unfortunate enough to have both cancer and massive burns. There are proteins that are unique to the interior of new blood vessels, and there have been therapies aimed at stopping angiogenesis. It seems fairly straightforward: cut off blood supply to tumors, and watch them regress. Well, going back to the analogy of NYC vs. Mumbai, tumor blood vessels can often be leaky or haphazard in organization, making delivery of anti-angiogenic drugs difficult. (Imagine the job difficulty of a UPS guy in Mumbai vs. NYC)

There exist anti-angiogenesis therapies, like Avastin . Although Avastin did not quite live up to its hype, there are better therapies in the pipeline to exploit the phenomenon of angiogenesis in cancer. In particular, there is a lot of potential for using targeted nanoparticles by several groups, including this one at the Moores Cancer Center.

If you have made this far, dear reader, then I hope this article has helped to paint a photo of how difficult cancer is to treat. But please do not mistake technical difficulty for pessimism. There WILL be better therapies for cancer that increase survival and lessen side effects.

Feel free to email me with questions.

-Ryon

Written by Ryon

November 13th, 2011 at 6:35 pm

Posted in Science Blog

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