Pancreatic cancer is a devastating disease with a generally poor prognosis, largely because it is usually detected in late stage disease where chemotherapy options generally have a limited effect. Typically response rates with gemcitabine are around 5%, with advanced patients living around 5-6 months on average. Erlotinib, an EGFR inhibitor, is also approved in the USA for treatment of the disease, but the therapy only adds approximately two weeks to survival. Many doublets and triplets have been tried and tested over the last 10 years, with little impact on survival. It was, therefore, exciting to see some young researchers presenting interesting and novel strategies at AACR this week to try and evade the resistance inherent in the disease.
Recently, Nab-paclitaxel (abraxane) has been granted orphan drug status in pancreatic and melanoma cancers. The rationale for using Nab-paclitaxel in pancreatic cancer is that it appears to weaken the stroma surrounding the tumour and also synergistically increases the effect of gemcitabine, the standard of care for the treatment of late stage disease when surgery is not an option.
Anirban Maitra presented a poster which showed how Abraxane targets the tumour stroma, depleting it, thereby reducing the impediment to chemotherapy. The Nab-paclitaxel works by utilising endogenous albumin pathways via binding of the albumin to secreted proetin acid rich in cysteine or SPARC. Interestingly, pancreatic cancer is known to overexpress SPARC and therefore offers a target for the drug.
In a Phase I/II trial presented earlier this year at ASCO by Daniel van Hoff, the median PFS with the combination was 6.9 months, and median OS was 10.3 months. To put this in context, gemcitabine alone usually gives an OS of around 5 months, so adding Abraxane doubled the overall survival, which is a lot in pancreatic cancer. Dr Maitra's research showed that this doubling of response occurred because there was a 3.5 fold increase in the amount of gemcitabine delivered in the tumour after the depletion of the stromal layer by Nab-paclitaxel.
This research therefore offers a fascinating insight into how other treatments could also be used in combination with Abraxane to potentially improve overall survival in this disease.
Two of the other interesting ideas came from a research group at the Massachusetts General Hospital here in Boston. The first one, presented by Tayyaba Hassan, took an out of box approach to rethink how to get a drug that has shown some modest efficacy in pancreatic cancer, bevacizumab, inside the cell. The drug is a VEGF inhibitor that typically acts on VEGF outside or on the ligand on the cell surface. It has limited efficacy in mopping up the VEGF this way, because getting past the stromal layer, as Dr Maira showed, severely limits drug access.
Hassan and her group decided to find a way to get the drug inside the cell to see if that would mop up more VEGF and induce a more durable response. They created a nanotechnology based delivery device to simultaneously deliver the bevacizumab and an FDA approved light activated chemical in the tumour cells in a mouse model. Photodynamic therapy (PDT) has been shown previously to improve treatment outcomes in pancreatic cancer. However, in clinical trials where standard chemotherapy was combined with bevacizumab, there was no benefit in survival. The theory was that perhaps not enough chemotherapy or monoclonal antibody therapy was getting through to mop up the VEGF and induce apoptosis in the pancreatic cells.
The results were highly interesting.
In the mice models, the nanotechnology device (nanocell) successfully delivered bevacizumab to the tumour cells and improved the acute response in the mice compared with those treated with bevacizumab alone. The combination with PDT was associated with even greater improvements.
The nanocell also delivered enough bevacizumab to cause a 2 fold reduction in metastasis to the lungs, liver and lymph nodes.
Phase I trials are due to begin in humans and the results will be eagerly awaited. If successful, the nanotechnology concept will offer a new and creative paradigm for delivering cancer drugs to the right place at the right time with greater effectiveness and less toxicity.
Prakash Rai and his colleagues at the MGH also looked at the possibilities with nanotechnology by combining it with photodynamic therapy (PDT) to simultaneously target the EGFR and MET pathway using cetuximab and PHA-665752:
The goal behind the approach was to reduce cross-talk and escape routes for the cancer cell, attacking several pathways at once is one way to do this. The end result is drug delivered more effectively inside the tumour cell and ultimately, a reduction in the tumour burden. It will interesting to see if there is a reduction in metastasis and overall survival.
This novel approach could potentially be applied to other drug combinations and tumour types and offers a new targeted method of getting larger amounts of drug inside the cancer cell, where it can do more damage.