Hitting Cancer True and Straight: the Role of Tissue Analysis
In August of 2023, I was contacted by a young woman with an extremely rare sarcoma. She was under the care of one of the most famous medical centers in the US and commuted from her home in upstate New York to Boston for treatment.
Although she showed some response, her disease persisted and she was being considered for surgery to remove the residual tumor in the stomach wall.
The Boston-based surgeons were disinclined to assist and offered only to remove the tumor but not send a portion to us.
Not to be dissuaded, she traveled to California under the care of a capable surgeon in LA to have the tumor removed and submitted to our lab.
The surgery went well and we received an excellent sample, enabling us to study a broad array of drugs, combinations, and targeted agents.
She then returned to the east coast.
In addition to our functional analysis we submitted a portion of tissue for next generation sequence (NGS) to look for genomic mutational drivers.
Long before the DNA analysis returned, we had completed our studies and one finding stood out.
There was an absolutely clear signal for drugs that target phosphatidylinositol kinase that regulates glucose and nutrient signaling. Both Alpelisib (PIK3CA) and Everolimus (mTOR) as well as the MYC-oncogene-active agents revealed strong activity, all part of the tumor’s ability to make and use energy.
I reported our EVA/PCD results in early September with a very clear suggestion that the genomic analysis would identify these same bioenergetic pathway abnormalities.
As many of you may be aware, we are now engaged in the study of human metabolism and increasingly believe that cancers are driven, not by genetic aberrancies, but instead by metabolic abnormalities. Here was a patient whose principal abnormality and sensitivity appeared to be metabolic.
On 10/16/2023, 6 weeks after our report was completed, the NGS report returned.
Low and behold, the two principal NGS findings were abnormalities of mTOR and PIK3CA, precisely what our assay had predicted. These are the exact targets of the small molecules we tested.
I contacted the patient to say how pleased we were that her genomic and phenotypic analyses agreed completely.
However, she explained that her treating physician in Boston was utterly disinterested in our findings and only cared to review the genomic profile.
Here was proof that our culture results were more discriminating, much faster and gave a much better indication of the likelihood of response, as patient benefit has been shown to correlate much more strongly with our results than with DNA profiling (Nagourney A Proc AACR, 2023).
Odysseus: A Metaphor for Cancer NGS
In Greek mythology, Odysseus, the hero of the Trojan War, returns home years later. His wife, left by herself all these years, had many suitors but she would have none of them unless they could string Odysseus’s bow and shoot an arrow through 12 ax handles. None of the suitors were remotely capable of the task.
Then a disguised and unrecognized Odysseus arrived, and in an instant, strung the bow and shot the arrow through the 12 ax handles, revealing himself to be the true hero.
The stringing of the bow and accuracy of the arrow were driven not by brute strength, but by dexterity and skill.
Modern medical oncologists rely increasingly upon brute-force next generation sequencing (NGS) in a feeble attempt to wrench information from DNA.
It is their hope that their patient’s genes can be tortured into confessing the secrets of effective therapy, but it is only functional biology provided by the study of human tumor explants that can provide the answers they seek; not through force but dexterity and skill.
It is our hope that the patient will be a candidate for one of the combinations we identified in her tissue studies. We have previously shown not only activity but also the synergy for Alpelisib combined with Everolimus (Nagourney, et al., Proceedings, AACR, 2019).
Will skill and dexterity prevail?
I certainly hope so.