PARP inhibitors more widely effective than previously thought

[Lani]

PARP inhibitors have been used against BRCA associated breast cancers and triple negative breast cancers, but now research (done in cell lines and with implanting cell lines derived from human tumors in mice only so far) shows them to be effective in a triple negative and ER+her2- cell line and safe, by not affecting normal breast cells or neural or heart cells. Unfortunately no her2+ cell line was utilized in this series of experiments. Let's hope that is their next step!

Survival of the healthiest

Selective eradication of malignant cells

The ultimate goal in cancer research, a treatment that kills cancer cells whilst leaving healthy cells untouched, is brought nearer by the success of a new therapeutic approach. The potential therapy, published in BioMed Central's open access journal Breast Cancer Research, targets proliferation of cancer, but not normal, cells.

An international research team led by Professor Cohen-Armon of Tel-Aviv University found that potent phenanthridine derived polyADP-ribose polymerase (PARP) inhibitors that were originally designed to protect cells from cell-death under stress conditions (e.g. stroke or inflammation), efficiently eradicate MCF-7 and MDA231 breast cancer cells without impairing normal proliferating cells, such as human epithelial cells (MCF-10A), nor normal non-proliferating cells, such as neurons and cardiomyocytes.

Human cancers depending on a constitutive activity of externally regulated kinase (ERK) were examined. The rationale for testing PARP inhibitors in these cancers was the recently disclosed up-regulation of ERK signals in the nucleus by activated PARP-1. However, other mechanisms are apparently involved. The phenanthridine PJ-34 caused a permanent G2/M cell-cycle arrest and cell death within 48-72 hours in breast cancer MCF-7 and MDA231 cells. In contrast, normal proliferating cells overcame the imposed G2/M cell-cycle arrest within 12 hours, survived and continued to proliferate.

In vivo, PJ-34 prevented the development of MCF-7 and MDA231 xenotransplants in nude mice without affecting their growth, development or behaviour.

Other PARP inhibitors were recently proved efficient only for treating relatively rare hereditary human cancers developed in individuals with an impaired DNA repair (BRCA gene mutation). However, in the current research, breast cancer cells lacking the BRCA mutation were efficiently eradicated.

According to Professor Cohen-Armon, "This research provides a new therapeutic approach for a selective eradication of abundant human cancers."

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Notes to Editors

1. A selective eradication of human non-hereditary breast cancer cells by phenanthridine derived polyADP-ribose polymerase inhibitors
Dana Inbar-Rozensal, Asher Castiel, Leonid Visochek, David Castel, Francoise Dantzer, Shai Izraeli and Malka Cohen-Armon
Breast Cancer Research (in press)

LINK:During embargo, article available here: http://breast-cancer-research.com/imedia/8631741972518752_article.pdf?random=650125

After the embargo, article available at the journal website: http://breast-cancer-research.com/

[Rich66]

Was wondering about PARPS for all. How about PARP + Hercep and Tykerb.

[gdpawel]

Small molecule enzyme (PARP) inhibitors may serve as a potent approach for prevention of BRCA related breast cancer. However, the use of this strategy for therapeutic treatment for hereditary breast cancers is dependent on the continued susceptibility of BRCA mutant cells to PARP inhibitors, which may be achieved by using a combination with other agents (Int J Med Sci. 2006: 3(4): 117-123).

Although the theory behind enzyme inhibitor targeted therapy is appealing, the reality is more complex. For example, cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to target multiple pathways in a cancer cell. Another challenge is to identify for which patients the targeted treatment will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and monoclonal antibodies).

Recent studies on targeted therapy have shown that tumors can become resistant to a targeted treatment. This means that the drug no longer works, even if it has previously been effective in shrinking a tumor. To solve this problem, new drugs are being designed or combined with existing ones to target the tumor more effectively.

The cancer state is typically characterized by a signaling process that is unregulated and in a continuous state of activation. These drugs promise to become an essential part of the physician's armament against cancer, particlarly those cancers that have developed resistance to other forms of treatment.

However, setbacks with drugs that specifically target specific pathways, reflect a lack of validated biomarkers. What is needed is to test the concept of targeted cancer drugs with biomarkers as pharmacodynamic endpoints, and with the ability to measure multiple parameters in cellular screens now in hand using flow cytometry.