New promising drug combination for end-stage lung cancer and terminal colon cancer patients

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.

Diagram depicting the difference between single agent therapy and combination
therapy. MEK inhibitor allone eventually leads to tumour growth, while MEK
and ERBBs inhibitors in combination lead to tumour cell death (apoptosis).
This diagram was copied from Cell.

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.

For info about Biozantium by Paeon Laboratories:  http://www.biozantium.com

In order to explain his research, the eloquently spoken professor, uses a road map as a metaphor, to demonstrate that there are several paths that lead from point A to point B. Where, the main route is perhaps the easiest and fastest way, but when it is blocked you will take the alternative (less convenient) route to get to point B. Inside a tumour the same principle applies. Tumours have a preference for a particular survival pathway. However, when you block that pathway (using drugs), a cancer will use an alternate route to survive. The trick is to block the preferred route and the alternative one simultaneously.

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

1. Patients with mutated KRAS CRC are unlikely to benefit from anti-EGFR therapy
2. Cetuximab and panitumumab (these are both monoclonal antibodies i.e. immunotherapy) demonstrate a survival benefit in patients with KRAS wild-type CRC
3. Cetuximab or panitumumab is no better than best supportive care alone for mutated KRAS CRC
4. 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
5. 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
6. 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:

1. 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
2. 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

1. 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).
2. 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.
3. 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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