When your genes make you superhuman.
By: Shivani Malik
Tags: Cancer, Cancer Treatments, Chemotherapy Drugs, Cancer Drugs, Chemotherapy

Photo by Kevin Bonilla on Unsplash

My sister and I used to wait for the whole week to watch a comic series called He-Man. Growing up in a small, sleepy town in North India, this was what fired the imaginations of our nine- and six-year-old minds. We didn’t mind the black and white pictures or the horizontal static lines that periodically flickered the screen for we were enthralled by superhuman strength of this man whose name itself spelled masculinity and vigor. My sister and I however quickly outgrew the charm-the superhuman valiant feats that He-man performed were just that -superhuman, hysterical strength beyond the realm of physical possibility.

Fast forward 3 decades and while our bodies still nowhere near performing the acts of He-man, there are instances when bodies of select few behave in extraordinary, unexpected ways such as exceptional response to cancer drugs which fail to make a mark on people with clinically similar cancer.

A few lucky ones: A small fraction of cancer patients mount a striking response to therapy surviving significantly longer than patients with clinically similar disease. The study discussed here explores the why.(Photo courtesy: Nil Roy)

What makes these rare people show super-human response to therapies that fail in thousands of others? This was the goal of a group of scientists from National Institute of Health (NIH) who profiled the tumors of such 110 exceptional responders using a multi-platform genomic approach. This means that the researchers looked at the genetics of these tumors using almost all available methodologies. Looking at what genes were mutated in these tumors was a no brainer. We know for a decade now that different genes are mutated in different cancers and many of these can be targeted by special drugs (targeted or precision medicine). The group then layered this genetic or DNA info with that of its message -genes transcribe into m(messenger)RNA -the intermediate that is made into proteins-the class that performs all the work in a cell. A faulty DNA will make a faulty RNA which in turn will make a faulty protein disrupting the function it performs in the cell. Finally, the group peered into the immune component of these tumors, looking into the composition of the immune cells circling the tumor cells, evaluating which ones could actually infiltrate the tumor. The group compiled all this information to ask-does any or all of this explain why these patients respond in such an exceptional way? The answer was yes in about ~23% of patients. For example, a patient with glioblastoma (a type of brain tumor) responded exceptionally to temozolomide (a kind of chemotherapeutic drug that alkylates the DNA). Most chemo drugs work by introducing DNA damage in rapidly dividing cells (rapid, uncontrolled division is the hallmark of cancer cells). Such DNA damage signals the cells to slow growth in order to repair their DNA. If the cells fail to repair their DNA damage, the cells opt to trigger a mechanism to kill themselves. Given such a catastrophic response in response to failure to fix DNA damage, a cell has many different ways of fixing all sorts of damage-a nick in the DNA is fixed by a specific pathway (single stranded DNA repair), a more elaborate DNA damage that introduces a gap, call the double stranded DNA repair service. The redundancies and fall backs of repair mechanisms is exploited by cancer cells which can find ways to fix their DNA and happily divide even in presence of chemo drugs that are bombarding attacks on their DNA. For example, the authors found that this super-responder Glioblastoma patient harbored mutations in not one but two or three different DNA repair mechanisms. Therefore, when clinicians gave this specific chemo drug, temozolomide, to this patient, its effects could not be countered by the inherent repair machineries of the tumor cells which had no other avenue but to kill itself in face of its with damage riddled DNA.

Another patient who responded exceptionally well to immunotherapy was because the patient had high numbers of natural killer cells which as the name suggests are good immune cells that eats away the bad cells which in this case is the tumor cells. In addition, the cancer of this patient also made a lot of specific chemical that in turn favored immunity against itself sparking an exceptional response to immune therapy that did not make a mark on another patient with same cancer.

A third category of super responders were those who harbored very high expression of two genes which could be directly targeted by drugs available in the clinic. Why did other patients didn’t respond to such targeted therapy? This specific breast cancer patient has expression level of the targetable gene which fell into the top 1.5% of all tumor samples-meaning the exceptional responder had exceptionally high level of gene that was driving the cancer train. The cancer was so addicted to this driver that once you shot it, the train derailed and crashed.

Finally, the fourth category of super responders were humans who had compound elements of the above three above categories, their DNA damage repair was faulty, they had a robust immune cell population surrounding the tumor and had a driver mutation that could targeted by a drug available in the clinic.

All of these patients had their bodies ravaged by aggressive cancers that wreaked havoc on their bodies and all aspects of life. They would be deemed unlucky by all definitions, but in a twist of fate their cancers evolved such that they could respond extraordinarily to therapy, adding in some cases, a decade to their time on earth. We are only beginning to understand what makes some of patients to respond super humanly to therapy. The challenge is to expand on these findings, find broader genetic patterns and strategize treatment tailored to these patterns to ultimately enable the majority, not a select few, to mount a superhuman response to therapy.

Source-

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment. Cancer Cell, 2020. PMID: 33217343