The big picture on our current research.

An anti-cancer peptide with broad specificity and no effect on normals.

Today’s post is a follow-up on our research in collaboration with Matthew Pincus.  The work is described in an earlier substack post and in our crowd-sourcing fundraiser on Experiment.com which we have decided to suspend. Partly due to poor response — we think that many people working in the field who are asking for popular support. On the positive side, we also decided that the project is far enough along that we can apply for foundation support or federal agencies. The big picture is still needed. Cell biology, and cancer especially, has great complexity, and I want to present the big picture. You can support the work here by subscribing to the substack.

Let’s start in the middle, the big take-home message: more than 20 years ago, Matthew Pincus, his students and coworkers synthesized a small peptide (15 amino acids). It turned out that the peptide, called PNC-27, was able to kill a surprisingly large number of different cancers.  Also unusual, PNC-27 showed no effect on normal cells. Surprising because it is common for a scholarly paper on the subject to begin by saying that there is no such thing as “cancer” but, rather, only a large number of individual cancers that were different in many ways.  A seminal review and follow-up on the “Hallmarks of Cancer” [1, 2] described generalizations, but the real hallmark is the diversity of cancers. PNC-27 killed a lot of them.

Also surprising was the limited effect of PNC-27 on normal cells. In some sense, cancer cells are normal—you might say that the defect is that they're too normal. The life of the cell involves growth and proliferation. Cancers over-grow their normal environment and can’t stop proliferating. The processes are sophisticated and highly structured and easily disrupted. It is not hard to kill cancer cells, but It is hard to protect normal cells in the process. There are many anti-cancer drugs. Most, however, have serious side effects and high toxicity. In cancer research, the controls are the big players.

The evolution of our understanding of the PNC-27 system has some detours, and the story of the discovery of its mechanism, described in the previous posts, is quite interesting. There was a moment, however, where we simply had a compound that would take out cancer cells and leave normal cells intact. You can see it for yourself. A scanning electron microscope will show you the surface of a cell. The figure below shows the effect of treating a cancer cell and a normal control with PNC-27. In the upper left panel you can see the regular slightly ruffled membrane of a MIA-PaCa-2 cell (human metastatic pancreatic cancer). The upper right panel shows that treatment of these cells with PNC-27 causes multiple transmembrane pores that are lined with spherical edges. The pores allow equilibration of the cell contents with the environment and death of the cell. The lower two panels show a normal AG13145 cell (a human fibroblast). Here, there is no effect of the compound. The smooth membrane of the untreated cell does not change after application of PNC-27.

Might PNC-27 be the magic bullet?

Isn’t PNC-27 what we wanted? A compound—relatively simple in structure, easy to make (once you go into production)—that kills cancer cells specifically. It does not affect normal cells. Beyond the wide variety of cells targeted in tissue culture, animal studies show that PNC-27 can eradicate pancreatic cancer and a cancer of the blood (acute myelogenous leukemia) without any negative side effects. So, why aren’t we charging ahead? Not easy to answer. Of course, a paraphrase of the question for a practicing scientist might be: aren’t these results sufficiently convincing for you to stop your current (possibly well funded) project and change direction? And there is the emotional reaction that it might be too good to be true. Thinking mechanism, the role of metabolism is only just coming out. There are also questions of total resources for funding research. But the data point us to real opportunities.

The flip side of the project.

A compound specific for cancer is only half the picture and half the opportunity. If we can attack cancer cells specifically, the cells must have a target on their back. And, we know what it is. It’s the protein HDM-2. That’s the state of affairs. We seem to have an anticancer agent and we know, contrary to so many tries before, the Achilles Heel of the cancer cell. I leave this as a broad picture. Details were in the previous posts or you can comment or ask a question.

And the keto angle.

The grand theme is still cancer as a metabolic disease. The role of the mitochondrion in the PNC-27 story is just beginning to be understood [3]. An early observation shows the effect of ketone bodies. The ability of ketone bodies, ketogenic diets, and ketogenic compounds to enhance the effects of drugs and other modalities is a consistent theme. The figure below shows the ability of ketone bodies to enhance the effect of PNC-27 on MCF-7 (breast cancer) cells in culture.   

The previous SubStack post and the content of our Experiment project has the details, the mechanisms, and our particular focus. And we laid out our immediate goal, which is fairly close to success—we think we have an improved method for detecting cervical cancer. Our previous discussion may not have been easy to understand.  Cell biology is a dark forest where even the trees are obscured. Hopefully, these comments will help with the big picture.

If you are interested in supporting this important research, consider becoming a paid subscriber. All of the proceeds go to the research described in this post and related work on ketogenic diets for cancer. We are grateful for all of your support.

References

1. Hanahan, D, Weinberg, RA (2000) The hallmarks of cancer, Cell 100 57–70

2. Hanahan, D, Weinberg, RA (2011) The hallmarks of cancer: the next generation. Cell 144 646–674

3. Krzesaj, P, Adler, V, Feinman, RD, Miller, AY, Silberstein, M, Yazdi, E and Pincus, MR (2024) Anti-Cancer Peptide PNC-27 Kills Cancer Cells by Unique Interactions with Plasma Membrane-Bound hdm-2 and with Mitochondrial Membranes Causing Mitochondrial Disruption. Annals of Clinical & Laboratory Science, 54, 137-148