[BBB/Neurosciences] Why chemo is less effective on brain cancers than other types of cancer?

This is a post that termed from a  message left by one follower on my Facebook asking me: why does chemo do no penetrate the blood-brain barrier?
This was indeed a very good question that surely many non-scientists may ask themselves but have little or no reply on that topic.
To understand why chemo do not penetrate the BBB, you have to understand the obstacle a chemotherapeutic agent has to cross to get inside the brain.
In order for any drugs to get into the brain, you have to cross the BBB. If you are a drug, you are sorted into two class: hydrophilic drugs and lipophilic drugs. Hydrophilic drugs are “water-soluble” and dissolve easily in biological fluids (blood, gastric juice…) by their own. The problem however is that such drugs cannot enter the cells unless they have a protein carrier, also named “transporter”, that can bring this drug inside.
The second class of drugs are lipophilic drugs. These are drugs that dissolve poorly in water and other biological fluids but dissolve very well in fat and oils. Because cell membrane are made of fatty acids and cholesterol (yep, that’s why we need cholesterol as we also use it to make bile salts to dissolve fats from our food and also as a prime brick for the production of steroid hormones), lipophilic drugs can passively diffuse through the cells and reach the target.
Thats a boon and a bane in the same time when you are in the drug discovery side. A boon because it means your drug will not have issues to get into its target and can be given orally, a bane because it is also mean these drugs will be substrate of drug efflux pumps.
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Drug efflux pumps are belonging to a super-family of molecules called “ABC transporters”. ABC stands for ATP-binding cassettes, as these pumps use ATP (Adenosine triphosphate, the major source of energy storage in cells) to function. These transporters function in a very similar fashion that exit door you can experience in a subway station: you can get from the subway system from it but you cannot get into the system from it.
Such efflux pumps were firstly described in cancer cells that developed drug resistance to their chemotherapy and later identified to be expressed by various tissues including intestine, liver and the BBB.
At the BBB, we have an array of different ABC transporters: ABCA (cholesterol efflux), ABCB1 (P-glycoprotein or P-gp), ABCCs (multi drug resistant polypeptides or MRPs) and ABCG2 (also called breast cancer resistant protein or BCRP). They have one job and only one job: to pump things out. Some have a very narrow spectrum (ABCA transporters mostly efflux cholesterol), some have such a broad spectrum (ABCB1 and ABCG2 share a common pool of substrates) that it is impossible to predict if your drug candidate will be substrate of these pumps or not. These pumps are so efficient to keep xenobiotics (any molecule not produced by your body) that we estimate over 95% of chemicals known by humans are not capable to cross the BBB. Thats a boon because many of these compounds can have severe neurotoxic effects, it is also a bane because it means that delivering drugs to the brain will be challenged by the BBB.
Unfortunately, a lot of chemotherapeutic agents have been shown to be substrate for one of these pumps. This has been recently brought into a white paper from the first  CNS Anticancer Drug Discovery and Development Conference (source:http://neuro-oncology.oxfordjournals.org/content/17/suppl_6/vi1.long)  co-authored by Dr. Quentin Smith (Texas Tech University Health Sciences Center, Amarillo, TX) and by William “Bill” Elmquist (University of Minnesota, St Paul-Minneapolis, MN), two eminent experts in the field of CNS tumors and BBB.
In 35 years of research, we have been able to extend the life expectancy of patients with glioblastoma multiform (GBM), one of the most aggressive type of cancer, from 7 months to 14 months. This is a fairly grim results in comparison to other types of cancer in which we are not talking about extending life expectancy but talking about how many patients stay cancer-free and overcome their cancer.
We certainly failed from bringing miracles to patients with brain cancer, but we are learning from our mistakes and by correcting them we are closer from finding better cures.
One mistake we have done was assuming that brain tumors were like any other tumors and were only good at making leaky and botched blood vessels. Turned out brain tumors surely make some botched blood vessels but they also find a way to keep chemotherapeutics away via the presence of a blood-tumor barrier (BTB).
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The second mistake was to consider that efflux pumps were equal in distribution and function, with a distinct preference for certain molecules.

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As you can see we have different pumps with an overlapping catalog of substrates but also an heterogenous activity, with P-gp and BCRP considered the main players. There are speculation that a rodent BBB and a human BBB are not similar in terms of activity of P-gp and BCRP (some studies suggest that the BBB in mice and rats rely heavily on Pgp, whereas in humans BCRP lift most of the weight). It also turned out that trying to block these transporters may have little or no advantages (http://onlinelibrary.wiley.com/doi/10.1038/clpt.2013.34/abstract;jsessionid=03AF5C34128C830A05FEDDF895E4A5B2.f02t04).
Finally, we are also learning that there is not such a “one size fits all” in brain tumors. Brain tumors are very heterogenous between their types and even between tumor sites within the same patient, as depicted in one figure presented in the white paper cited above.
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You can see that the uptake of 17 different compounds between a healthy brain region and a tumor brain were poorly correlating to each other.
Therefore, a lot of scientists are working on to find way to circumvent this issue. One approach is to enhance our odds to remove the tumor during surgery by using a glowing tag to label brain tumors (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343207/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343207/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343207/) and depicted below:
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Some try to develop some Trojan horses to bypass the BBB and deliver the chemo directly inside the brain and some try to basically transiently open the BBB by using micro bubbles in combination of focused ultrasounds (FUS) that induce a local dilation of these bubbles and a small opening of the BBB.
Science is a long learning process made of high expectations and a high number of failures, bringing scientists back to square one in the design of new treatments. Brain tumors are certainly the worst and as a BBB scientist that collaborated on some aspect and attended a couple of international conferences discussing brain tumors, it is heartbreaking to have little or no options that we can offer to patients.
However, as we learn from our mistake, we are understanding that success will not come for a magic bullet but indeed by small incremental steps bringing us closer to a treatment for these particular types of cancer.

 

 

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