Chemotherapy_bottles_NCI

by Zachary Hauseman
figures by Michael Gerhardt

The cure for cancer: something we all hear about but never seems to arrive. It’s easy to get frustrated about decades and decades of research while thousands of people still succumb to the disease daily [1]. However, recent cancer treatments offer exciting potential for the field of cancer therapeutics in the future.

Cancer is a complicated illness that should be classified as a vast set of related diseases, which can often be quite different, [2] rather than a single disorder. At its core, cancer is an illness where cells become inadvertently “selfish,” meaning that they begin to grow and divide in a way that can be harmful to the surrounding tissues and organs. Cells generally become selfish when genes important for growth or survival become mutated.

Historically, it has been easiest to think about cancer in terms of where it originates: breast, colon, or pancreatic cancer, for example, and in fact, this was once how cancer was exclusively defined. However, it is now possible to use genetics or physical features of cells to create a more complete description. With today’s technology in gene sequencing and other diagnostics, we can know exactly how the genome of a cancer cell compares to healthy cells in other parts of the body.

This has been an important development, as different mutations will result in very different cancers with different optimal treatments. Therapy for cancer is now shifting towards drugs that will affect a very specific feature of the patient’s cancer instead of chemotherapy, which is designed to generally kill all fast-dividing cells.

Chemotherapy and the Idea of Cytotoxicity

Though cancer can be relatively unique across individuals, all cancers tend to have some common characteristics, such as rapid growth and division. This has allowed the medical field to design drugs that have been successful in helping some patients live longer or even completely remove their tumors without knowing all the details or mechanisms of how the cancer developed [3].

Every treatment for cancer has to be “targeted” in the sense that it helps to selectively remove cancer cells and leave healthy tissue relatively unharmed. Cancer cells are in most respects just like normal cells, and accordingly, anything harmful to a cancer cell will also be likely to hurt healthy cells. Nonetheless, the general strategy for combatting cancer for some time has been a targeted version of what can be considered cellular poison: cytotoxic drugs that affect only rapidly-dividing cells. Let’s look at an example to illustrate this point: Taxol.

Taxol (or paclitaxel) is a drug originally isolated from the Pacific yew tree. It specifically targets rapidly dividing cells by attacking the process of cell division itself. Taxol works by freezing cells’ structural fibers, called tubulin, that are critical for normal cell division [4,5] (Figure 1).

Taxol is detrimental to cancer cells in tumors that are growing fast and splitting constantly, but it also affects regular hair follicles, the digestive tract, and bone marrow, all of which are normal populations of cells that happen to divide quickly. In general, Taxol can be given to patients only at certain doses. This “therapeutic window” is the range of doses where the drug gives a positive effect on disease without unacceptable toxicity. However, unlike an ideal drug, there are severe side effects related to the vulnerable tissues: hair loss, vomiting, diarrhea, and joint or muscle pain. These side effects are sometimes enough to prevent doctors from prescribing high doses that could be necessary to remove all of the cancerous cells, leaving open the possibility that leftover cells may grow into tumors again in time [5].

Figure 1. Microtubules are part of the skeleton of each cell and are required for a cell to divide. Microtubules are made up of many repeating building blocks that come together and dissociate depending on the scenario. Taxol freezes microtubules in place by preventing the individual units from coming apart, thus affecting cells that are rapidly dividing. 1, 2: Individual building blocks first form repeating chains that eventually form the microtubule. 3a, 3b: Microtubules remain together when in use and can break down into their original building blocks once their job is done so that they can perform new jobs. 3a is blocked by Taxol.

The Targeted Therapy Revolution

So how can this problem be solved? Much more is known about cancer now than just a few years ago. This provides the opportunity to target our drugs towards more specialized aspects of cancer besides rapid growth. For example Imatinib and Venetoclax are two drugs that aim to target proteins only expressed in cancer cells.

Imatinib (or Gleevec) is a drug known as a kinase inhibitor [6]. A kinase is a special type of protein that has the ability to make chemical “marks” on other proteins or itself (Figure 2), which is a common way that cells make and propagate signals. Sometimes, a process like growth can be regulated by kinases marking other proteins as a sort of “on” switch. When these kinds of kinases get mutated in such a way that causes them to turn on growth processes when they’re not supposed to, this can cause cancer.

In some forms of chronic myelogenous leukemia (CML), a genetic mistake causes two genes to become connected to form a new cancerous kinase (Figure 2) [6,7]. This mutation causes two unrelated genes to fuse together to code for BCR-ABL1, a protein kinase that does not normally exist. The BCR-ABL1 kinase is actually responsible for the cancer itself and is thus called oncogenic.

Recall that Imatinib is a kinase inhibitor, which means that it specifically stops the BCR-ABL1 from adding the “on” switch and causing cancer. Imatinib is a great example of a targeted cancer drug because it affects a protein that only cancer cells have, reducing the negative effects of this therapy. Imatinib was approved by the FDA in the early 2000’s and ushered in a new trend of effective targeted therapy [6,8].

Figure 2.
Left: A kinase is a protein that adds phosphate “marks” to other proteins, or even itself. To do this, it takes a phosphate group from another molecule, ATP, and places it on the protein that will be marked. These marks signal for processes like cell growth, and when too many are applied they can result in cancer.
Right: One form of chronic myelogenous leukemia (CML) is caused when two chromosomes swap regions to form a new gene (black arrow). In this cancer a new protein results from the fusion of the BCR and ABL1 genes.

A second and more recent example of this modern strategy for targeting cancer is a current phase three clinical trial candidate. This drug, called Venetoclax [9,10], has passed through multiple rounds of tests in humans confirming its safety and initial promise for treating Chronic Lymphocytic Leukemia (CLL). If further tests confirm that the drug is effective, it could be on the market within a few years.

Venetoclax works by reactivating apoptosis, or programmed cell death, in cancer cells [9,10]. Apoptosis is a normal biological process and is important for keeping healthy cells around and removing unwanted or unhealthy ones [11]. When a normal cell’s DNA gets damaged, that cell often dies rather than risk becoming cancerous [11].

To control this process, all cells have sets of both pro- and anti-apoptotic proteins that balance whether the cell lives and dies. When a signal tells the cell that it’s time to die, the pro-apoptotics are activated. However, to prevent too many cells from dying by accident, anti-apoptotic proteins can keep their counterparts from doing their job. Only once the active pro-apoptotics outnumber the anti-apoptotics can cell death progress.

Because of DNA damage and other signals, cancer cells already have activated pro-apoptotic proteins that would otherwise kill the cell. Certain cancers, such as Follicular Lymphoma [9], make an unusually high number of anti-apoptotic proteins to avoid cell death even though the cell’s existence is dangerous. Venetoclax is able to block these anti-apoptotic proteins and tips the balance of apoptosis to reactivate cell death in cancer cells. Since normal cells never received stress signals in the first place, they remain generally unharmed (Figure 3).

Figure 3. P indicates pro-apoptotic protein, A indicates anti-apoptotic protein.
Left: Cells in a normal state have un-activated pro-apoptotic proteins and thus are firmly biased towards staying alive.
Middle: When a cell gets stressed, its pro-apoptotic proteins get activated. If the stress causes the number of active pro-apoptotics to outnumber ant-apoptotics, it will undergo cell death.
Right: Cancer cells have stress signals that activate pro-apoptotic proteins, however they overproduce anti-apoptotic proteins to keep the scale from tipping towards death. Venetoclax can stop some of the anti-apoptotics from working and thus lets the balance shift back to apoptosis.

Jimmy Carter and Keytruda

Another new class of cancer drugs are “immunotherapy” drugs. Former president Jimmy Carter recently made news by declaring that his brain tumors had shrunk to an undetectable level—a good outcome for his advanced melanoma [12]. The drug that he claimed caused this remission was Keytruda, a part of this new class, though surgery and radiation he received also likely helped.

Keytruda has shown potential in helping the immune system take on tumors [13] by overcoming one of the tricks that cancer cells use to hide themselves from the immune system. Tumor cells need to look normal and healthy to avoid being destroyed, so they often display PD-L1 (Programmed death ligand 1), a protein that prevents immune system attack [14-16]. This is an important mechanism for keeping normal cells safe during inflammation but also keeps the immune system from recognizing a tumor it would otherwise attack.

Keytruda, unlike the other drugs mentioned before, is actually a protein itself. This drug is an antibody against PD-L1 [13], so it physically covers up the signal that protects cancers cells. Immunotherapy is a growing field and is another example of important ways that cancer can be targeted with new and creative mechanisms.

What Does All This Mean for Cancer in the Future?

We still do not have ideal drugs, and problems with the therapeutic window and side effects of cancer drugs are not yet completely solved with current targeted therapies. Despite this, adding new ways to fight cancer is always a positive and has given doctors new options for treating patients, especially those whose cancer does not respond to traditional chemotherapy. Bringing actual drugs to the public takes many years; for example Venetoclax was designed based on initial discoveries made in the 1990s [17] and still needs further clinical development and FDA approval.

Despite how slow this process can be, we are already seeing the advent of therapies that make many types of cancers more manageable. What these examples show is that there is a major shift is occurring the ways that we treat cancer—a trend that gives the cancer therapy field a lot to look forward to.

Zachary Hauseman is a graduate student in the Chemical Biology program at Harvard University.

References

1. Cancer Statistics. 2015; Available from: http://www.cancer.gov/about-cancer/what-is-cancer/statistics.

2. What is Cancer? 2015; Available from: http://www.cancer.gov/about-cancer/what-is-cancer.

3. Gustavsson, B., et al., A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer, 2015. 14(1): p. 1-10.

4. Barbuti, A.M. and Z.S. Chen, Paclitaxel Through the Ages of Anticancer Therapy: Exploring Its Role in Chemoresistance and Radiation Therapy. Cancers (Basel), 2015. 7(4): p. 2360-2371.

5. Socinski, M.A., Cytotoxic chemotherapy in advanced non-small cell lung cancer: a review of standard treatment paradigms. Clin Cancer Res, 2004. 10(12 Pt 2): p. 4210s-4214s.

6. Zhang, L.I., et al., Imatinib-based therapy in adult Philadelphia chromosome-positive acute lymphoblastic leukemia: A case report and literature review. Oncol Lett, 2015. 10(4): p. 2051-2054.

7. Fielding, A.K. and G.A. Zakout, Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Curr Hematol Malig Rep, 2013. 8(2): p. 98-108.

8. Musumeci, F., et al., Analogs, formulations and derivatives of imatinib: a patent review. Expert Opin Ther Pat, 2015: p. 1-11.

9. Cang, S., et al., ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol, 2015. 8(1): p. 129.

10. Roberts, A.W., et al., Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. New England Journal of Medicine. 0(0): p. null.

11. Renehan, A.G., C. Booth, and C.S. Potten, What is apoptosis, and why is it important? BMJ : British Medical Journal, 2001. 322(7301): p. 1536-1538.

12. Fox, M. Here’s a Look at Keytruda, the Drug Jimmy Carter Says Made His Tumors Vanish. 2015; Available from: http://www.nbcnews.com/health/cancer/heres-look-keytruda-drug-jimmy-carter-says-made-his-tumors-n475561.

13. Raedler, L.A., Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously Treated Unresectable or Metastatic Melanoma. American Health & Drug Benefits, 2015. 8(Spec Feature): p. 96-100.

14. Marquez-Rodas, I., et al., Immune checkpoint inhibitors: therapeutic advances in melanoma. Ann Transl Med, 2015. 3(18): p. 267.

15. Munn, D.H. and V. Bronte, Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol, 2015. 39: p. 1-6.

16. Jacobs, J., et al., Immune Checkpoint Modulation in Colorectal Cancer: What’s New and What to Expect. J Immunol Res, 2015. 2015: p. 158038.

17. Sattler, M., et al., Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis. Science, 1997. 275(5302): p. 983-6.

Cover Image: By Unknown photographer/artist, National Cancer Institute [Public domain], via Wikimedia Commons

One thought on “New Directions for Cancer Therapy: Targeted Medicine

Leave a Reply

Your email address will not be published. Required fields are marked *