TDM-1 for treatment of breast cancer

About a decade ago, a patient diagnosed with cancer, had a few options. If the disease was localized, (at one spot only), and could be surgically removed, it was resected. If surgery was not an option the patients were either given localized radiation therapy or their bodies were flushed with chemotherapy drugs that indiscriminately attacked more or less all cells in the body. If the cancer was metastatic, i.e. spread across multiple sites, chemotherapy was the preferred course of action. But the unwanton targeting of all cells in the body led to extreme side effects including hair loss, extreme fatigue and fertility issues resulting in overall reduction of the quality of life of patients.

But in the past decade and a half, the pharmaceutical companies have veered away from one shoe fits all strategy by developing treatment options tailored to the patient’s disease. These therapies take in account the genetic component of the disease (genes being shut down, proteins being over-produced etc.) and specifically target those cells. The EMILIA study published in the New England Journal of Medicine in October 2012 studies the safety of one such therapy[1].

In about 20% of the breast cancer cases, a protein called human epidermal growth factor receptor 2 (HER2) is over-produced and present on the cancer cell surface[1]. Currently, these patients are treated with a combination of trastuzumab and taxane. While trastuzumab is an antibody (a protein that mimics the body’s immune system) and targets the cells that express HER2, taxane destroys microtubules, the cell machinery needed for dividing cells[2].

For patients whose disease is advanced and spread to multiple sites and couldn’t be contained by conventional treatments, a combination of capecitabine (a DNA blocker) and lapatinib (an inhibitor of the HER2 pathways) is used. Scientists at Genentech developed an alternative therapy called trastuzumab emantisine (TDM-1) which links the HER2 antibody trastuzumab with the microtubule destroying derivative drug of maytansine (DM-1) that is toxic to cells[1]. The EMILIA study compares these two therapies for patients whose disease has progressed on trastuzumab and taxane.

Scientists found that for patients receiving TDM-1, the cancer did not grow for an average of 9.6 months versus 6.4 months on capecitabine and lapatanib. Also, fewer patients (40.8%) reported serious side effects than those on capecitabine and lapatinib (57%). The most common side effects for patients getting capecitabine and lapatinib, were sever diarrhea (20.7%) and hand-foot syndrome(16.4%), i.e. the swelling, redness and tenderness of palms of hand and feet. In contrast, the side effects of TDM-1 patients were decreased platelet count(12.9) and increased liver function(4.3%), both controlled by modification of drug regimen.

TDM-1 therapy thus provides patients with an alternative option.

1. Verma et. al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. The New England Journal of Medicine. October 1, 2012 DOI: 10.1056/NEJMoa1209124
2. Bullock et. al. Clinical Efficacy of Taxane–Trastuzumab Combination Regimens for HER-2–Positive Metastatic Breast Cancer. The Oncologist May 2008 vol. 13 no. 5 515-525.

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Improving Interferon Therapy for Relapsing Multiple Sclerosis

As humanity continues its onslaught of attacks against the various diseases that have debilitated countless for millennia, the stockpile of the weaponry we use is constantly evolving. For thousands of years, people depended mainly on plant extracts for curing their maladies. Then came the age of man-made compounds. Today, we stand at a precipice where the man-made therapies are designed to harness or hijack the disease producing pathways or to mimic internal body response to disease.

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Deep Impact

On the first day of the new semester at the University of Southern California, as I made my way to Organismal Biology and Evolution class, there was a flurry of activity around campus: people on bikes, on skateboards and on foot. The 300-seat auditorium in Taper Hall of Humanities began to fill with a steady stream of undergrads, spots of color propping up in an otherwise grey and white auditorium. Within 5 minutes, the room was bustling with activity, friends greeting one another, strangers getting acquainted, laptops and notebooks being taken out and Ipods being switched off. The sleepy young tanned bodies that occupied the seats contrasted the pale jovial man with salt-n-pepper hair, Dr. David Hutchins, on his laptop, under two giant projector screens in the front.

As the clock struck 10, Dr. Hutchins looked over his glasses and in a clear loud voice, introduced him and the course; sudden silence took over the room. Anxious note taking had begun, most students sitting at the edges of their seats, backs hunched, scribbling and typing what seemed like every word of his. Next to me was a guy in his late twenties, with bags underneath his eyes, scrolling through early morning news. From my position in the back of the auditorium, I saw at least 20 Facebook pages open in front of me. How I missed being a carefree undergrad!

The parentheses around Dr. Hutchins’ cheeks were replaced by a somber expression as he introduced the first topic; large bold red letters on the projector screen read Global Warming. A Time magazine cover, ‘Be Worried, Be VERY Worried’, bore broken arctic ice and a helpless polar bear staring at its reflection. Bright orange sun and solar flares graced the cover of the Newsweek with ‘Global Warming is a hoax’ in white print. At the center of the screen, the book titled ‘Global Emergency’ carried a blue earth engulfed in orange-red flames. The blond boy in front of me, still oblivious, was reading the latest blog entry by Perez Hilton.

Sitting there, I wondered if these new voters had realized what they were in for. Would these 50 minutes affect their views on Environment Protection Agency? A quick show of hands revealed about a quarter of the 300 odd-freshmen believed in global warming, most were ambivalent and there was one, who did not. All eyes were on the brunette in green.

Promising an unbiased presentation of scientific facts, Dr. Hutchins spoke of the history of earth; early on, our atmosphere was dominated by carbon dioxide (CO2) and methane, while all oxygen was in bound form i.e. combined with other elements. With the appearance of life as photosynthetic archaebacteria (archae=ancient), atmosphere changed; archaebacteria consumed CO2 for energy and released free oxygen (O2), i.e. oxygen not bound to other elements, into the air as their waste. Over time, the free oxygen levels increased, facilitating the evolution of aerobes. The brunette cringed at the word. “We have a non-believer”, I smiled.

The advent of industrial revolution accompanied rapid deforestation; more CO2 was being produced, lesser recycled into O2. The graph on the screen showed a near constant increase in the atmospheric CO2 levels from the stable values before 1750’s, about 35% (from 280ppm to 380ppm) over 300 years, measurements made by drilling Antarctic ice cores and analyzing trapped air bubbles.

Dr. Hutchins smiled as if he read the question on everyone’s mind: “So what?” He went on to explain that just as glass panes trap heat inside a greenhouse, so do gases like CO2 and methane. Increasing CO2 leads to more heat being trapped, resulting in higher annual temperatures recorded throughout most of the world, a trend that parallels the rise of atmospheric carbon dioxide. There were whispers and oddly a chuckle.

Talking about rising sea levels, Dr. Hutchins showed the projected coastline of the United States with submerged New York City, Washington DC and entire states of Florida and Delaware. Cheerfully he pointed out, that scientists could not predict the time scale of this scenario, but when it happens, at least the politicians would be under water. There was laughter. A self-identified Miami resident moved uncomfortably in his seat. Dr. Hutchins continued about melting of continental ice due to increasing temperatures, adding water to already swelling oceans (remember, water expands on heating). Where will this water go? The land we live on, he exclaimed.

Addressing the skeptics of human hand in global warming, Dr. Hutchins’ spoke about ocean acidification. Most in the class had never heard of this phenomenon, neither had I. An equation on the screen showed how CO2 in the air dissolves in water forming carbonic acid. Increasing CO2 levels have led to an increase in the acidity of both Atlantic and Pacific oceans, as measured by decreasing pH values recorded over last two decades. Just as carbonated soda slowly chips away calcium carbonate in the tooth enamel; acidification of ocean waters slows down the rate of growth of the protective shells of crustaceans, mollusks and foarms, the base of the aquatic food pyramid. High temperature and low pH kills coral reefs. Imagine the havoc on the oceanic ecosystem, he said.

As I sat there, vivid images of the future made me eerie. Tuvalu, a Pacific island-nation would become inhabitable during my lifetime! The Great Barrier Reef will disappear!

I was brought into the present by the clangs of folding desks that shattered the silence of the past hour. Murmurs emerged as laptops were shut down and books were stuffed into bags. It was 10.50AM, the herd of freshmen rushed to their next class. I wonder of the influence this class had on these minds? For now I was happy to see them scoot away on their bikes and skateboards, but come Saturday how many will choose to ride the Metro to Santa Monica Beach? I tried to catch up with the brunette in green, but alas, she was gone!

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