New Drug for Triple-Negative Breast Cancer

by Gregory Pawelski | February 14, 2011 12:44 PM EST

As our understanding of breast cancer biology continues to advance, this disease has come to be understood as many different diseases. As seen with PARP inhibitors, mutations work with other proteins. Genes do not operate alone within the cell but in an intricate network of interactions.

Original categorizations based on histology lead to lobular versus ductal subtypes. Thereafter, recognition of estrogen and progesterone status, and finally HER2 status provided further subcategorizations.

Over the past decade, molecular subtypes have characterized this disease into a series of signatures characterized by luminal, basal and other groupings with distinct prognoses. Within the context of these categories, the triple negative breast cancers have emerged as an important target.

These patients whose tumors do not mark for estrogen, progesterone, or HER2 on immunohistochemical or FISH analyses, appear to carry features that segregate them into a BRCA1-like biology. This is of great interest clinically for it offers the opportunity to treat these patients with drugs found active in the BRCA mutant populations.

Among the most active drugs in these patients are the PARP inhibitors. The excellent results with PARP inhibitors and BRCA mutants have been followed by striking response and survival data combining PARP inhibitors with carbo-platinum and gemcitabine. PARP inhibitors by inhibiting DNA damage response can enhance the effects of ionizing radiation, mustard alkylators, topoisomerase inhibitors, platins, and intercalating agents.

At cell-based, functional profiling labs, they've explored the biology of PARP inhibitors in breast and other cancers. In these investigations, the labs apply the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

To date, they have observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients, and in some triple negative patients. More interesting, will be the results combining the PARP inhibitors with mustard alkylators, platins, and drug combinations to optimize PARP inhibitor combinations.

This work is ongoing in triple negative and BRCA positive patients as well as other tumor types where the PARP inhibitors may prove useful in the future. The PARP inhibitors are turning out to be very useful, but you don't have to enter a clinical trial to find that out.

by Raghu Pandurangi | February 10, 2011 7:00 PM EST

It is great to include DNA repair inhibition as an additional biological paramter in clinical settings  for an added therapeutic index.  However, it can be noticed that PARP is also nonselective inhibiting the normal cell repairs which is why side effects may persist.

One can design PARP inhibition targeted to cancer cells based on the biomarker.  Additionally, conventional chemotherapy induces predominantly necrosis pathway for cell death which may trigger the cascade of inflammatory response since the intracellular debris are poured into the system.

It may be worthwhile to detour the cell death by apoptosis which is well orchestrated phenomenon. Again, every thing should have a targeting component built into it.

In my opinion, unless we do not block multiple avenues for cancer growth, we will continue to have incremental benefits and not significant benefits. Combination of PARP inhibition with chemo may be in the right direction. considering the other avenues such as dysregulation of apoptosis, hypoxicity forbidden drug delivery, angiogenesis  etc...

Still, long way to GO!!

Thanks for sharing my views;

Raghu Pandurangi, Ph.D.