Saturday, December 17, 2016


From Aristarchus of Samos’ 3rd century BC geocentric concepts to Copernicus and Galileo to Johannes Kepler’s heliocentrism, science is always in a state of exploration and flux. Whether it is in the Newtonian mechanics of force and gravity to the Quantum mechanics of ethereal entanglements, humans have dared to go further, taking the road less travelled. Today’s scientific world, bowing at the altar of evidence seems forcing itself into an exile of the ossified “what is.” Yet evidence is fluid and ever-changing. Today’s evidence is tomorrow’s discard.

What if we could harness the miseries of cancer by turning on and off genes? Well that has been done. What if we could shut down pathways from the surface of the cancer cell to its innards; the nucleus, and stop it from dividing? Done that too. What if we could suppress the oncogenes that trigger the cancer cell growth? Done that as well. What if we could grow a battalion of tumor suppressor genes within the cell to prevent its doubling and dividing? Well we seem to be there now. And what if we could shut down the cargo proteins from transporting material in and out of the cells to allow them to bloat and die? We might be there as well. You see, don't you, that science progresses on the shoulders of giants in a drip, drip fashion; one idea igniting another thought and then another and then empiricism begins...if one would allow it, that is. (BTW: I have NO Conflict of interest with the Karyopharm Therapeutics). 

A drug called Selinexor (KPT-330) made by Karyopharm Therapeutics seems to fit the bill. It has been used in Multiple Myeloma with significant results in previously heavy-treated patients with Multiple Myeloma and found a 20% Response Rate. That may not appear significant unless one thinks about the previous heavy therapeutic exposure. (STORM Trial Data). Additionally Selinexor has been used in Diffuse Large B-Cell Lymphoma and initial reports are seeing benefits there as well. “To date, Selinexor has been administered to more than 1800 patients across company-sponsored and investigator-sponsored clinical trials. Evidence of single-agent anti-cancer activity has been observed in many patients and Selinexor has been sufficiently well-tolerated to allow several of these patients to remain on therapy for prolonged periods. Over 20 patients have remained on study for over 12 months, with the longest patients on study for over 24 months” (1). In the solid tumor world there are reports of Selinexor having some impact in Sarcomas. (2).

Another mode of action being utilized by the same pharmaceutical agency is to inhibit the cargo protein transit. Two products, PAK4 and NAMPT “causing co-inhibition by catalyzes the rate-limiting step in one of the two intracellular salvage pathways that generate nicotinamide adenine dinucleotide, or NAD. NAD is a universal energy- and signal-carrying molecule involved in mitochondrial function, energy metabolism, calcium homeostasis, anti-oxidation, and paradoxically generation of oxidative stress, gene expression, immunological functions, aging, and cell death. leads to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis.”

So harnessing the tumor suppressor elements and blocking the cargo movement shuts down the process of cell division. In biz terms it would be like a block in the supply chain of materials, inventory drops, revenue diminishes and sustainability is questioned.

This brings me back to the premise of using “evidence” as a hard and fast rule in treating patients. Science is continuously evolving due to exploration and discovery. The limits are only those of the limits of thought. Maria Sklodowska better known as Marie Curie who founded the science of Radioactivity, twice a Nobel winner continued to work in refining the knowledge till her last breath. Evidence to her was a snapshot in time of what we know at the moment. The "why" always tinkered with her thought process and pushed her into her intellectual grist mill. So today's well versed bureaucrats constantly serving the "public's best interests" seem to forget what made today's progress and achievements. Limiting progress under the guise of guidelines and templates to achieve uniformity thus limits the art and stifles the science of science and medicine.

The two examples above are how progress flows, never in a straight line but through tortuous paths hitting pay-dirt sometime and sometime just dirt. The idea to illustrate such principles of thought needs historical background and a future unseen but imagined foreground. To limit our knowledge within the pages of books is akin to imprisonment of the soul of discovery. Our thoughts and ideas need to skim the surface of information and thus enter the depth of newer spheres. Perhaps we should consider the innovator, discoverer in all of us physicians and continue to explore venues unseen, unheard and unknown rather than punch time clocks, check boxes and fill our eyes with the glow of the flickering computer screens.

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