Jin Park ‘18, THURJ Staff

Cancer, a group of diseases which has plagued humans since the beginning of mankind, has remained largely misunderstood for most of history. Due to recent advances though, we now know that cancer is fundamentally a genetic disease, and can be characterized by a set of hallmarks that were described in a pivotal paper written by Hanahan and Weinberg more than a decade ago (Hanahan, Weinberg, 2000). These include the ability to stimulate growth of blood vessels and tumor cells, the ability to metastasize, and resistance towards inhibitory signals and apoptosis. These characteristics make cancer not only deadly in many cases, but also incredibly difficult to treat.

The past few decades have seen a shift in paradigm in terms of cancer treatment, in which scientists are learning more about the unique molecular characteristics and tendencies of tumor cells, and can subsequently direct therapeutics to exploit those mechanisms. This is a far cry from some of the first cancer treatments. The first forms of chemotherapy were quite literally poisonous chemicals—the US Army, in its examination of the nature of chemicals of warfare used in WWII, found that nitrogen mustard worked as a treatment of lymphoma. This agent served as the model for treatments (broadly called alkylating agents) which kill rapidly growing cells by damaging DNA beyond repair.

According to the American Cancer Society, until the 1990s, this type of therapy was largely the only form of treatment against cancer. However, recently, with the discovery of drugs such as imatinib, which exploits a specific proteomic abnormality in cancer cells that distinguishes them from normal cells of the body, scientists have been able to target treatments to tumorous cells more efficiently. Targeted therapies now include inhibiting telomerase to preclude cancer cells’ ability to replicate indefinitely, and aerobic glycolysis to cut off tumors from their primary source of carbon.

Among the plethora of targeted therapies, PARP inhibitors (PARPi) show genuine promise in the fields of breast and ovarian cancer. Yet in order to understand how PARPi works, we must first have a basic understanding of the fundamentals of our genetic code.

Our DNA is unstable, and we might see this instability as a vestige of evolutionary pressure to quickly adapt to environmental fluctuations in the distant past. Nevertheless, our cells still have mechanisms set in place to regulate the relatively uncommon errors in DNA. One property of cancer cells is unlimited replicative potential, and cancer cells frequently harbor defects in DNA repair pathways, which confer the genomic instability to allow such unregulated growth. It is crucial to note that although cancer cells take advantage of the fact that major DNA repair pathways have been knocked out, this can serve as a potential target for therapeutics that drive DNA damage to force cancer cells to commit to apoptosis.

There are four main DNA repair mechanisms in the cell: base-excision repair, nucleotide-excision repair, mismatch repair, and recombinational repair—which includes homologous recombination (HR) and non-homologous end-joining (NEHJ) (Underhill, et. al., 2011). The first three are responsible for correcting single strand breaks (SSBs) in the DNA, while the last is mainly reserved to correct double strand breaks (DSBs).

Single strand breaks (breaks or nicks on only one strand, where the other strand is left intact) are the most common DNA impairment, and about 10,000 SSBs occur in each cell every day (Lindahl, et. al., 1993). These lesions are corrected primarily via the base-excision repair pathway, which includes a family of proteins called poly(adenosine diphosphate) —ribose polymerases (PARPs) which plays a critical role in the repair of the DNA (Underhill, et. al., 2011). Simply put, when single stranded DNA damage occurs, PARP binds directly to the lesion and produces large branches of poly (ADP-ribose), as its name suggests. These branches help recruit DNA repair enzymes that can repair the lesion. While SSBs can be corrected using the other strand as a template, DSBs necessitate repair primarily by homologous recombination, which repairs DNA with fairly high accuracy (Hoejimakers, 2001).

When PARP activity is lost in cells, they employ the HR pathway to correct the SSBs that would normally have been corrected through one of the other pathways reserved for correcting SSBs. With this knowledge in hand, it becomes feasible to exploit this deficiency in cancer therapy—that is, if tumor cells that are already deficient in critical proteins involved in the HR pathway (such as the proteins BRCA1 or BRCA2) were to be targeted with PARP inhibitors, cancer cells could be forced into irreparable DNA damage. The critical factor which allows PARP inhibitors to function as an effective treatment is that some cancer cells also lack mechanisms to fix double strand breaks. This includes the 5-10% of patients with BRCA1 and BRCA2 mutations, common in those suffering from breast cancer. In these patients, tumors are BRCA-defective, the HR pathway is also defective, and therefore treatment with PARP inhibitors will lead to accumulation of double strand breaks, which eventually become lethal for the cell.

The key idea here is that treating patients with PARP inhibitors is a form of targeted treatment because in non-tumorous cells, even if we inhibit PARP, the cell has a functional HR pathway to fix single strand breaks. However, cancer cells rely on PARP to fix its SSBs, which, if left unfixed, can lead to DSBs.

PARP inhibitors could comprise efficient treatments for various patient subpopulations in cancer. In addition to breast cancer patients, this therapy may even be useful for cancer patients without a BRCA mutation because of potential interactions with other treatments. For instance, when chemotherapy is used to treat ovarian cancer, the current standard is cisplatin. This drug causes DNA strands to crosslink with each other, and PARP inhibitors prevent the cancer cells from fixing these breaks. This can increase the amount of cancer cell death. Thus, there is a potential for BRCA positive patients to benefit from PARP inhibitors, as using PARP inhibitors can decrease tumor burden by increasing the effectiveness of the chemotherapy.

Indeed, this concept of “synthetic lethality” was first introduced by Theodosius Dobzhansky in 1946, where a “mutation in one of two genes individually has no effect but [when combined with the other] leads to cell death” (Underhill, et. al., 2011). Exploiting this with regards to cancer cells has shown promise in both bench research and in patients, where many PARP inhibitors have proceeded to Phase 3 clinical trials. Currently, there are 111 clinical studies involving PARP inhibitors as reported by the NIH, and this number seems to increase quite frequently. Many PARP inhibitors are also now given as part of a combined therapy with drugs such as temozolomide, an oral chemotherapy drug.

There is overwhelming evidence that PARP inhibitors may be effective for patients with or without HR pathway deficient cells. In breast and ovarian cancers, PARP inhibitors are the perfect example of personalized cancer medicine, where a patient’s unique cellular characteristics are being used in the fight against cancer. The next steps are to determine whether cancer cells can develop resistance to PARP inhibitors and whether this therapy can become the new standard of care for some cancers. Current research seems to suggest that cancer cells cannot develop resistance to these inhibitors, but only time will tell whether this is true.


Hanahan, Douglas, and Robert A. Weinberg. “The Hallmarks of Cancer.” Cell 100.1 (2000): 57-70. Web.

Underhill, C., M. Toulmonde, and H. Bonnefoi. “A Review of PARP Inhibitors: From Bench to Bedside.” Annals of Oncology 22.2 (2011): 268-79. Web.

Hoeijmakers, Jan H.J. “Genome Maintenance Mechanisms for Preventing Cancer.” Mechanisms of Ageing and Development 128.7-8 (2007): 460-62. Web.




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