Chemo - kinase inhibitor combination therapy clinical trial for drug resistant lung- and colon-cancer patients
Recently, Sun and colleagues (working in the lab of Professor Rene Bernard at the National Cancer Institute – Antoni van Leeuwenhoek in the Netherlands), developed a new combination therapy for drug resistant lung- and colon-cancer patients. The results of near inhibition of tumour growth look very promising. They published their in vitro and in vivo (pre-clinical) results in Cell (a scientific journal).
In contrast, mainstream cancer therapy is currently
unable to offer such a successful treatment for end-stage lung or colon cancer.
It is
estimated that approximately 30% - 50% of colorectal tumours (20% of lung
cancer patients) have a mutated (or abnormal) KRAS
gene. A quantitative PCR technique to test for this mutation is often utilised
to determine if patients with ColoRectal Cancer (CRC) might respond to anti-Epidermal
Growth Factor Receptor (EGFR) antibody therapy (i.e. those patients with
wild-type KRAS). However, 40% to 60% of patients with wild-type KRAS tumours do not respond to these biologics (antibody
therapy). In these patients, data suggest that a mutation in the BRAF gene, which is present in 5% to 10% of tumours, is
perhaps responsible for this lack of response to treatment.
Mutations in signaling pathways fueling tumor growth and cancer spread - Do all roads lead to Rome?
KRAS mutations on the other hand are even more difficult
to address, given that there are no treatments available to target KRAS directly.
However, there are drugs, which have already been approved for use in the
mainstream cancer care setting, that are capable of targeting those proteins
that are affected and de-regulated as a result of abnormal KRAS activity. Unfortunately,
when you administer these drugs individually to a patient they have a relatively
weak effect on disease outcome. This is where Professor Rene Bernards and his
team hope to make a difference. They came up with the idea to look for specific combinations of drugs to treat cancer patients on the basis of the genetic make-up of the tumour (i.e. personalised medicine) in order to generate a
durable response.
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For info about Biozantium by Paeon Laboratories: http://www.biozantium.com |
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Combination therapy (MEK inhibitor Selumetinib and EGFR / ERBB2 inhibitor Afatinib)
results in drastic reduction of tumour growth (Sel+Afa). This graph was copied from
Sun et al., 2014. |
After several elaborate experiments, Bernards’ team
discovered that lung and colon cancer cells with a KRAS mutation can be
effectively targeted with the combination of a MEK inhibitor, such as
Selumetinib (please see diagram next to
text) and an EGFR / ERBB2 pathway inhibitor (e.g. Afatinib or Dacomitinib). The
in vitro as well as in vivo studies (pre-clinical studies with mice) produced
very promising results (see a copy of one of the graphs from Professor Bernards’
research on the right).
Where can you get access to this drug combination cancer therapy?
The facility (National Cancer Institute – Antoni van
Leeuwenhoek) where this research was conducted, is a research centre with an
integrated cancer hospital unit. The institute’s objective is to translate scientific
research into clinically applied therapies as soon as possible. This integrated
approach has led to a successful collaborations between scientist professor
Rene Bernards and medical professional Dr Jan Schellens.
Dr Jan Schellens (oncologist) will start a clinical trial
to test the combination therapy (for which professor Rene Bernards’ findings
form the basis) in April 2014. Apparently, some patients have already been
recruited / enrolled into the study, but there a few places are still available
(given that this is likely to be a small phase I study, I suspect that there
will not be many places available).
Please see below the contact details for Dr Jan Schellens
in case you need further information on how to enroll in this study.
Dr Jan
Schellens has his clinic at the Medische Oncologie department.
The address
of the Netherlands Cancer Institute (Nederlands Kanker Instituut) is as
follows:
Department of Medical Oncology
Netherlands Cancer Institute
1066 CX Amsterdam
The Netherlands
Phone #
+31 20 512 2446
Fax # +31 20 512 2572
Email: j.schellens@nki.nl
Some clinical implication of KRAS/BRAF status
- Patients with mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy
- Cetuximab and panitumumab (these are both monoclonal antibodies i.e. immunotherapy) demonstrate a survival benefit in patients with KRAS wild-type CRC
- Cetuximab or panitumumab is no better than best supportive care alone for mutated KRAS CRC
- Cetuximab plus FOLFOX (fluorouracil + leucovorin + oxaliplatin) is more effective in achieving a greater response rate and lower risk of disease progression in KRAS wild-type compared with mutated KRAS CRC
- Cetuximab plus FOLFIRI (fluorouracil + leucovorin + irinotecan) improves survival and response rate in KRAS wild-type compared with FOLFIRI alone, while mutated BRAF was associated with a poor prognosis
- Panitumumab plus FOLFOX4 study data suggest a reduced survival in patients with mutated KRAS
Example of a laboratory test available for checking KRAS/BRAF status:
- The therascreen KRAS RGQ (Rotor-Gene Quantitative) PCR (polymerase chain reaction) Kit will test for mutations in codons 12 or 13 of the KRAS gene on formalin-fixed, paraffin-embedded tissue from the primary tumor or a metastasis
- For BRAF mutation status, either a PCR amplification coupled to a DNA sequence analysis or allele-specific PCR for BRAF V600E mutation status on formalin-fixed, paraffin-embedded tissue from the primary tumor / metastasis will be performed
Clinical aspects of Selumetinib and how this MEK inhibitor works
- Selumetinib (also known as AZD6244, or ARRY-142886) acts on two kinases in order to reduce the activity of the MAPK/ERK pathway (i.e. Selumitinib blocks the enzyme MAPK kinase (MEK), which is located immediately downstream of BRAF - please see diagram at the top).
- The drug selumetinib is highly selective and blocks the sub-types MEK1 and MEK2 of this enzyme, but does not target p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Phase 1/2.
- Several clinical trials investigating Selumetinib are being conducted in cancer patients with non-small cell lung cancer, or NSCLC, thyroid cancer, melanoma, ocular melanoma, hepatocellular cancer, colorectal cancer, pancreatic cancer and breast cancer.
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Something to consider for patients with KRAS mutant tumors
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