Restart

It is quite easy to get used to fasting.  It is equally easy to get unused, if there is such a word.  I last ate 24 hours ago, and I’m not liking it one bit.  As always, I’m not hungry, but I’m already irritable, and I can’t wait for this to end.  Before my three-week break, I breezed through the first day of fasting without any discomfort.  Now I have two and a half days without food ahead of me, and I’m questioning the wisdom of it.  Eating is good.  Enjoying food is good.  Depriving myself of it might have some speculative and unsubstantiated value for me, which is why I will follow through with it, but it doesn’t make me happy.

On Wednesday, if everything goes as I imagine it, I will start my third chemotherapy program.  It’s not much different from the first two.  The main ingredients, 5-fluorouracil and folinic acid, are the same.  The antibody is different.  It’s unlikely that a new antibody will make a striking difference to a failed therapy.  I will still submit to this therapy with eagerness and even joy.  It’s the only thing I have, it should, at the very least, slow the growth of the tumors, and it just might be more effective than what I’ve braved so far.  There’s no reason to start this with anything but unjustified optimism.

Instead of an anti-VEGF antibody, I will get one against EGFR.  Despite being a titled biochemist, I have only a vague understanding of the difference.  Antibodies themselves are relatively clear.  They are a class of proteins in the shape of a Y that specifically recognize short protein motifs for the purpose of eliminating intruders such as viruses and bacteria.  They can be raised against native proteins and, if they block interactions important in diseases, are candidates for development into drugs.

EGFR is the epidermal growth factor receptor.  I don’t know much more than the name tells me.  This receptor sits in the cell membrane and receives growth signals in the form of epidermal growth factor (EGF), a small protein.  VEGF is vascular epithelial growth factor.  I can’t say much beyond the fact that it is also a protein and has something to do with blood vessels.  Time to do some reading.

Growth factors, such as EGF and VEGF, regulate cellular metabolism, promote cellular growth and can stimulate tumor cell proliferation.  Tumor cells secrete VEGF to promote the growth of new blood vessels which will supply the tumor with the nutrients required for continued growth.  Anti-VEGF antibodies probably bind to VEGF and prevent its interaction with its receptor, thus breaking the signalling mechanism.  In theory, a lack of new blood vessels should prevent new metastases from taking hold.  This didn’t work for me.

EGFR is a bit different.  When activated, this receptor stimulates a signaling cascade that contains RAS proteins, of which KRAS is one.  KRAS in turn stimulates RAF kinase, which upregulates various metabolic activities.  The G13D mutation in KRAS – the amino acid glycine at position 13 in the protein sequence is changed into aspartate – goes a long way in explaining my cancer.  A paper I mentioned a long time ago claims that “protein synthesis and cell proliferation were significantly higher” in KRASG13D cells.  The paper also shows that KRASG13D cells were “highly transcriptionally responsive to EGFR activation”.  This might explain that EGFR inhibition is beneficial in KRASG13D cancers.  In three months we will know if this had an effect in my case.

Unfortunately, the connection between KRASG13D and EGFR inhibition is not as clear as I thought at first.  An intriguing paper explained why EGFR inhibition might work in cancers with the KRASG13D mutation when it doesn’t work in cancers with a mutation in residue 12 of KRAS.  This rationalized results from a retrospective analysis of phase 3 clinical trial data that showed a benefit of EGFR inhibition for patients with KRASG13D.  The problem here is that it compares the reaction of patients with wild-type KRAS and KRAS mutated in residue 12 with patients with KRASG13D cancers.  What should have been compared is KRASG13D cancers with EGFR inhibition versus KRASG13D cancers with VGEF inhibition.  On second thought (or a proper reading of the literature) there is no indication that EGFR inhibition is any better than VGEF inhibition.

A less than enthusiastic report in literature is no reason to drop a therapy.  I will try anything until it proves itself to be worthless.  Fasting, much hyped in certain quarters, has not made the difference for me.  Maybe the EGFR antibody will.