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Oncology

Breast cancer

Breast cancer is the second most common cancer worldwide and the most frequent in women, both in developed and in developing countries. According to recent estimates, 1.67 million new cases were diagnosed in 2012 (25% of all cancers)1. It ranks as the firth cause of death from cancer overall, the first in less developed countries and the second, after lung cancer, in industrialised regions2.

In Italy it accounts for 29% of all cancer forms that affect women, with a mortality rate of 16% of all deaths for oncological causes3. Approximately 37,000 new cases are diagnosed every year, with growing incidence from south to north4. Although targeted treatments have been developed, to date these approaches have not proved effective for all cancer forms. One form of breast cancer cannot be treated with targeted drugs, because the neoplasm cells do not have specific receptors. This type of breast cancer is known as triple negative and accounts for 12-17% of all breast cancers5.

The only treatment currently available for this form is chemotherapy, whose results are not particularly satisfactory as it seems to facilitate the development of cancer stem cells (CSC), which preserve within themselves all the instructions to produce new neoplasm formations, and as such are a main cause of disease progression, development of metastases and relapses after treatment. Cancer stem cells represent roughly 2% of total cancer cells, and biologically their replication capacity is extremely high. They support cancer growth through their self-renewal ability, which is completely independent of the body's control systems.

Recent research studies identified cytokines, and in particular Interleukins-6 and -8 (IL-6 and IL-8), as potential targets for the development of innovative therapies able to act directly on the CSC, both in initial phase and in advanced or metastatic cancer forms. The objective of Dompé's research is to identify treatment solutions able to fight this particularly aggressive form of cancer.

Breast Cancer - Discover the Infographic

Reparixin: innovation from Dompé's research

In oncology, Dompé is developing a range of molecules that target specific and innovative cellular or biological mechanisms that have the potential of opening new perspectives in the treatment of some of the most common types of cancer. Reparixin, a product of Dompé research, is currently in Phase 2 development in patients with triple negative breast cancer.

Precursor of a new class of anti-cancer candidate drugs, reparixin explores a new therapeutic approach for triple negative breast cancer, based on potential action on CSCs. Treatment with Reparixin aims at changing the microenvironment in which CSCs replicate, hence ensuring a better control of the disease. In earlier trial phases reparixin was proven to be able to reduce CSC population both in vitro che in vivo6. The molecule's action in animal models induces a delay in cancer development and slows down the progression of metastases.

How reparixin acts

Reparixin influences the replication of CSCs by inhibiting the inflammation caused by Interleukin-8 (IL-8 or CXCL8): an essential step in the inflammation process, because it facilitates the inflow of white blood cells and their activation in the different body tissues. Two different IL-8 (or CXCL8) receptors are currently known: CXCR1 and CXCR2, expressed by the neutrophil white blood cells. Recent data demonstrate that the same receptors are essential factors for the modulation of cancer cell development7. In particular, the results of further studies suggest a possible impact of the control activity of CXCR1 on CSCs8.

The original mechanism of action of reparixin could find a future application in the study of other neoplasms, e.g. pancreatic cancer9. Moreover, it has been observed that silencing the CXCR1 and CXCR2 receptors inhibits the growth of melanoma and cancer cell dissemination10.

Ongoing studies

The molecule is currently under evaluation in various international trials
  • Phase Ib clinical trial to evaluate the safety and pharmacokinetic profile of oral Reparixin, administered in combination with paclitaxel in women with metastatic breast cancer (completed in 5 centres in the United States). The study is been completed and the preliminary results were presented at the 2014 ASCO Annual Meeting11.
  • Pilot clinical study to evaluate the effects of oral reparixin monotherapy on CSCs and on the cancer microenvironment in women with early-stage breast cancer before surgery (9 Centres in the USA).
  • Phase II clinical study (fRida): the objective of this trial is to evaluate progression-free survival after treatment with oral reparixin in association with standard therapy with paclitaxel compared with treatment with paclitaxel associated with placebo in patients with metastatic triple-negative cancer, after relapse of the disease following prior (neo)adjuvant chemotherapy. The study will involve 190 patients in 65 centers in US, Belgium, France, Italy, Poland, Czech Republic and Spain.

References

  1. Source: Globocan IARC-WHO, Breast Cancer Estimated Incidence, Mortality and Prevalence Worldwide in 2012
  2. Source: Globocan IARC-WHO, Breast Cancer Estimated Incidence, Mortality and Prevalence Worldwide in 2012
  3. Source: http://www.airc.it/tumori/tumore-al-seno.asp / consultato in data 15/04/2015
  4. Source: http://www.legatumori.it/page.php?id=1052&area=955 consultato in data 15/04/2015
  5. Source: William D. Foulkes, Ian E. Smith, Jorge S. Reis-Filho, Triple-Negative Breast Cancer, N Engl J Med 2010; 363:1938-1948
  6. Source: C. Ginestier et al., CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts, J Clin Invest. 2010;120(2):485–497. doi:10.1172/JCI39397
  7. Source: Waugh DJ et al., The interleukin-8 pathway in cancer, Clin Cancer Res. 2008 Nov 1;14(21):6735-41. doi: 10.1158/1078-0432.CCR-07-4843
  8. Source: C. Ginestier et al., CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts, J Clin Invest. 2010;120(2):485–497. doi:10.1172/JCI39397
  9. Source: L. Chen et al., The IL-8/CXCR1 axis is associated with cancer stem cell-like properties and correlates with clinical prognosis in human pancreatic cancer cases, Sci Rep. 2014; 4: 5911. doi: 10.1038/srep05911
  10. Source: S. Singh,Small-Molecule Antagonists for CXCR2 and CXCR1 Inhibit Human Melanoma Growth by Decreasing Tumor Cell Proliferation, Survival, and Angiogenesis, Clin Cancer Res. 2009 Apr 1;15(7):2380-6. doi: 10.1158/1078-0432.CCR-08-2387
  11. Source: AF. Schott et al., A phase Ib study of the CXCR1/2 inhibitor reparixin in combination with weekly paclitaxel in metastatic HER2 negative breast cancer – First analysis, Poster presented at 2014 ASCO Annual Meeting