Pharma Strategy Blog

I’m a subscriber to Science Translational Medicine and one of the things I really like about it is finding little gems like this – shared by Science Magazine on Twitter:

Breast cancer drug lapatinib boosts effects of apoptosis-inducing drugs in colorectal cancer

On clicking the link, I was delighted to see it was from Dr Wafik El Deiry’s group at Penn State, Hersey – you can find him as @weldeiry on Twitter – he tweets interesting snippets from various cancer conferences that he attends, including ones in GI cancers.

Here’s the essence of the paper that caught my eye:

We found that lapatinib improved the proapoptotic effects of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab.

Tumors from mice treated with a combination of lapatinib and TRAIL exhibited more immunostaining for cleaved caspase-8, a marker of the extrinsic cell death pathway, than did tumors from mice treated with lapatinib or TRAIL alone.

Mapatumumab (HGS via Cambridge Antibody Technology) and lexatumumab (HGS) are both monoclonal antibodies that target the TRAIL receptor 1 to induce apoptosis (programmed cell death) as shown in the cartoon below:

Source: Human Genome Sciences

Put simply, death receptors (DR) are cell surface receptors that transmit apoptotic signals initiated by specific ligands such as Fas ligand, TNF alpha and TRAIL. They play an important role in apoptosis and can activate a caspase cascade within seconds of ligand binding. Induction of apoptosis via this mechanism is therefore very rapid.

To date, few of the DR or TRAIL inhibitors have lived up to their promise and lexatumumab also seems to have disappeared from HGS’s pipeline after being returned by GSK in 2008.  Interestingly, there were some data previously published at ASCO in 2007, showing activity in a phase Ib trial in solid tumours due to synergy with gemcitabine, pemetrexed, doxorubicin or FOLFIRI:

Severe adverse events considered at least possibly related to lexatumumab included anemia, fatigue and dehydration. Tumor shrinkage has been observed, including confirmed partial responses (PRs) in the FOLFIRI and doxorubicin arms.

It looks as though mapatumumab is the successor to lexatumumab.  Early studies with mapatumumab have been reported in a phase Ib trial in HCC and phase II in NSCLC although the latter did not support further development in that indication.

What does the current research show?

I was wondering what the possible underlying mechanism for the synergistic effect might be, given that lapatinib (Tykerb) is known to be a HER2/EGFR inhibitor.  It does seem that this main target is not involved here though:

Lapatinib up-regulated the proapoptotic TRAIL death receptors DR4 and DR5, leading to more efficient induction of apoptosis in the presence of TRAIL receptor agonists. This activity of lapatinib was independent of EGFR and HER2.

In other words, the effects are off-target and unrelated:

The off-target induction of DR5 by lapatinib resulted from activation of the c-Jun amino-terminal kinase (JNK)/c-Jun signaling axis.

Of course, another EGFR inhibitor, the monoclonal antibody cetuximab (Erbitux) has been shown to work in refractory colorectal cancer and is approved in EGFR+ mutated disease.  Lapatinib, as far as I know, has not shown any clinical activity in colon cancer to date, but is approved for treatment of refractory HER2+ breast cancer in combination with capecitabine.

Sometimes, it can take a while to figure out the logical combinations and tumour types though.  This new research shows that, at least preclinically, there may be value in combining mapatumumab with lapatinib in colorectal cancer:

This activity of lapatinib on TRAIL death receptor expression and signaling may confer therapeutic benefit when increased doses of lapatinib are used in combination with TRAIL receptor–activating agents.

Implications of this research

A quick check of current clinical trials with mapatumumab shows that there aren’t any ongoing in colorectal cancer, but this research may well offer a strong rationale for the novel combination with lapatinib to be considered.

Of course, there is some wry amusement that the original TRAIL inhibitor, lexatumumab, was returned by GSK and lapatinib is marketed by the same company.

References:

Dolloff, N., Mayes, P., Hart, L., Dicker, D., Humphreys, R., & El-Deiry, W. (2011). Off-Target Lapatinib Activity Sensitizes Colon Cancer Cells Through TRAIL Death Receptor Up-Regulation Science Translational Medicine, 3 (86), 86-86 DOI: 10.1126/scitranslmed.3001384