Combining PARP inhibitors with existing cancer drugs promising

[News]

Ovarian and breast cancer treatments being developed that mix a protein inhibitor and traditional anticancer drugs are showing signs of success, according to a new review for Faculty of 1000 Biology Reports.

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[gdpawel]

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

The cell is a system, an integrated, intereacting network of genes, proteins and other cellular constituents that produce functions. One needs to analyze the systems’ response to drug treatments, not just one or a few targets (pathways).

In the functional profiling platform, where they can understand how PARP inhibitors enhance the effects of drugs and drug combinations, the excellent results with PARP inhibitors and BRAC 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. To date, they have observed good activity for the PARP inhibitors as single agents in BRAC1 positive patients, and in some triple negative patients.

At Rational Therapeutics, Inc., in Long Beach, California, they’ve explored the biology of PARP inhbitors in breast and other cancers. In these investigations, the lab applies the functional profiling platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations.

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 BRAC 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 necessarily have to enter a clinical trial to fine that out.

http://www.rationaltherapeutics.com/

http://healthinfoispower.wordpress.c...linical-study/

[Rich66]

Pan-tastic.

[gdpawel]

The Weisenthal Cancer Group has posted a client's email which described Gemzar + Cisplatin + Avastin was synergistic in her assay performed two and a half years ago. She said she did the treatment recommended by the assay. That was after she had no response on the "standard" of care, ACT.

She learned from her oncologist that the most current clinical research on Triple Negative Breast Cancer is showing that platinum is having a huge positive effect on killing those cancers. In addition, for women who are BRCA positive, they are using PARP inhibitors with great success.

[gdpawel]

The Sunday, April 3, 2011, experimental and molecular therapeutics poster session at the AACR 102nd annual meeting included Dr. Robert Nagourney's Rational Therapeutics presentation on signal transduction inhibitors. Using MEK/ERK and PI3K-MTOR inhibitors he explored the activities, synergies and possible clinical utilities of these novel compounds.

The findings were instructive. First, it saw a good signal for both compounds utilizing the Ex-vivo Analysis of Programmed Cell Death (EVA-PCD) platform (functional profiling). Second, it saw disease-specific activity for both compounds. For the MEK/ERK inhibitor, melanoma appeared to be a favored clinical target. This is highly consistent with expectations. After all, many melanomas carry mutations in the BRAF gene, and BRAF signals downstream to MEK/ERK. By blocking MEK/ERK, it appeared that his lab blocked a pathway fundamental to melanoma progression. Indeed, MEK/ERK inhibitors are currently under investigation for melanoma.

For PI3K inhibitors, the highest activity was observed in uterine cancers. This has interest, because uterine carcinomas are often associated with a mutation in the PTEN gene. PTEN is a phosphatase tumor suppressor that functions to block activation of the PI3K pathway. Thus, mutations in the tumor suppressor unleash PI3K signaling, driving tumors to grow and metastasize. Blocking PI3K provided a strong signal, indicating that this approach may be very active in tumors associated with these oncogenic events.

The third point of interest in the report was, perhaps, its most important. Specifically, that the lab can explore those diseases where MEK-ERK, PI3K and mTOR signaling are less established targets. Cancers of the lung, ovary, colon or breast all manifested profiles of interest. When they combined both pathway inhibitors in a process called horizontal inhibition, renal cell carcinoma popped up as the best target. These results, though exploratory, suggest a superior approach for drug development, allowing the lab to identify important leads much faster than the clinical trial process.

Source: Rational Therapeutics, Inc.

Poster from Rational Therapeutics Session at 2011 AACR Meeting

http://robertanagourney.wordpress.co...-aacr-meeting/

[gdpawel]

Poly ADP ribose polymerase (PARP) is a nuclear enzyme associated with response to DNA damage. Following single strand DNA breaks, the enzyme attaches a backbone of ADP and ribose that serves to initiate DNA repair. Certain classes of chemotherapeutics, specifically alkylating agents, can induce injury that results in extensive poly ADP ribosylation resulting in the exhaustion of intercellular pools of NAD and ATP ultimately leading to cell death.

Although PARP inhibitors have recently entered the clinical cancer literature mostly relating to the treatment of BRCA+ and triple negative patients, neither PARP nor PARP inhibitors are new to the cancer researcher community, according to Dr. Robert Nagourney, medical director at Rational Therapeutics, one of the pioneers of the functional profiling technique.

His group first became interested following a 1988 study by Distelhorst from Case Western Reserve (Distelhorst CW, Blood 1988 Oct;72(4):1305-09) that described a mechanism of cell death that correlated with their work in childhood leukemia. Previously, investigators at Scripps Clinic had described PARP’s role in response to 2CDA (Seto, S., et al. J Clin. Invest. 1985 Feb;75(2):377-83). His group has studied small molecule inhibitors of PARP for many years, and more recently, they have expanded these investigations to include BSI201 (iniparib) and AZD2281 (olaparib). Both of which are undergoing clinical investigations. Nagourney will be reporting their findings with these PARP inhibitors at the 2011 ASCO meeting (Nagourney, R., et al Proceedings Amer Soc Clin Oncol. 2011).

PARP inhibitors are easily studied and provide interesting signals in the tissue studied. They have seen activity in BRCA+ patients and some triple negative breast cancers. They have also identified synergy with other classes of drugs. The compounds are a welcome addition to the cancer therapy armamentarium and continue to be actively studied in the cell-based functional profiling platform.

Of interest is the recent failure of the iniparib plus Carboplatin & gemcitabine Phase III trial to meet progression-free and overall survival goals in triple negative breast cancer patients (Zacks Investment Research on January 31, 2011). This failure may reflect the need to apply predictive methodologies to select candidates for these drugs, similar to Nagourney's successful work with other classes of compounds.