Pharmacy Perspectives - Fall 2011 - 5

F A C u Lt y

CU	Pharmacy	Professor	 	 	 discovers	new	colon	cancer	marker
By Lisa Marshall

Decades-old research on alcohol metabolism helped lead to discovery
An	enzyme	originally	studied	for	its	ability	to	 metabolize	alcohol	and	other	toxic	compounds	 in	the	body	could	someday	play	a	critical	role	 in	the	development	of	new	tests	and	drugs	for	 colon	cancer,	according	to	a	research	team	led	 by	CU	School	of	Pharmacy	professor	Vasilis	 Vasiliou,	PhD. In	a	groundbreaking	paper	published	in		 January	in	the	journal	Biochemical and Biophysical Research Communications, Vasiliou	 reports	that	a	form	of	the	enzyme	Aldehyde	 dehydrogenase	(ALDH1B1)	was	found	in	high	 concentrations	in	39	out	of	40	colon	cancer	 specimens	studied,	suggesting	that	it	may	be	a	 remarkably	strong	biomarker	for	the	nation’s	 third-most	common	cancer. “If	this	is	what	we	believe	it	is,	it	could	vastly	 improve	both	the	detection	and	treatment	of	 colon	cancer,”	says	Vasiliou,	a	professor	of	 molecular	toxicology	and	a	nationally	renowned	 expert	in	ALDH.	 CU	Pharmacology	Professor	Emeritus	Richard	 Deitrich,	PhD,	helped	pioneer	the	study	of	 ALDH	in	the	late	1960s	on	campus	when	he	 began	to	look	at	one	version	of	the	enzyme	in	 the	very	different	context	of	alcohol	intolerance.	 ALDH2	breaks	down	alcohol	into	the	more		 benign	acetic	acid	(vinegar).	But	those	with		 genetic	mutations	which	prompt	them	to	run	 short	on	the	enzyme	have	trouble	processing	 alcohol,	and	tend	to	get	drunk	faster,	flush,	or	 get	sick,	says	Sam	Zakhari,	PhD,	director	of	 the	National	Institute	on	Alcohol	Abuse	and	 Alcoholism.	(Of	note:	The	drug	Antabuse,	used	 to	encourage	alcoholics	to	abstain,	works	by	 inhibiting	ALDH2	enzyme	expression	and,	consequently,	making	people	sick	when	they	drink.)	 With	funding	from	the	NIAAA	and	elsewhere,	 Vasiliou	has	spent	15	years	researching	the	 various	functions	of	the	important	family	of	 detoxifying	enzymes.	To	date,	19	genes	that		 encode	for	them	have	been	identified	–	each	 with	diverse	physiological	responsibilities.	In		 recent	years,	several	ALDH1	enzymes	(similar	 but	distinct	from	ALDH2)	have	been	found	to	 be	abundant	in	the	stem	cells	that	fuel	breast,	 lung,	ovarian,	prostate,	and	pancreatic	cancers.	 However,	none	have	been	expressed	so	densely	 or	strongly	as	ALDH1B1	in	colon	cancer	cells.	 “In	normal	tissue	in	the	colon,	this	enzyme	is	 present	only	in	a	few	cells,	but	once	the	cancer	 starts	developing,	every	single	cancer	cell	 expresses	it	at	really	high	levels,”	says	Vasiliou.	 “They	were	glowing	with	it.” Not	counting	skin	cancers,	colon	cancer	is	the	 third	most	commonly	diagnosed	cancer	in	the	 United	States,	with	101,700	new	cases	annually	 and	49,000	deaths.	Survival	rates	hover	around	 74	percent	for	stage	I	and	drop	to	6	percent	 by	stage	IV,	according	to	the	American	Cancer	 Society,	so	–	as	with	any	cancer	–	early	detection	 is	critical. While	it	is	5	to	10	years	away,	Vasiliou	believes	 physicians	could	someday	test	for	the	presence	 of	ALDH1B1	in	blood	or	feces,	as	an	adjunct	 to	or	in	place	of	a	colonoscopy.	In	the	realm	of	 drug	treatment,	he	envisions	a	sort	of	“suicide	 pill”	which	the	defensive	enzyme	inside	the	 cancer	cells	would	devour	and	metabolize	into	 something	that	would,	in	turn,	cause	the	cell		 to	self-destruct. Lingering	questions	remain:	Are	these	enzymes	 fueling	the	cancer,	or	just	a	beacon	of	its		 existence?	Could	testing	for	ALDH	mutations	 offer	insight	into	cancer	risk?	Could	there	be	a	 link	between	the	way	people	metabolize	alcohol	 and	their	risk	of	certain	cancers?

“If this is what we believe it is, it could vastly improve both the detection and treatment of colon cancer.”
The	answers	remain	uncertain,	says	Vasiliou,	 but	the	team	is	forging	ahead. It	has	developed	a	mouse	model	that	lacks	 the	ALDH	gene	to	see	how	it	responds	when	 exposed	to	cancer	cells,	is	studying	compounds	 that	bind	to	the	enzyme,	and	is	working	to	 expand	the	trial	to	include	thousands	more	 samples. Meanwhile	Zakhari,	whose	agency	has	been	 funding	ALDH	research	for	years,	says	he	is	 excited	about	the	surprising	places	it	is	leading. “All	of	this	sprouted	from	our	understanding	of	 how	alcohol	is	metabolized	in	the	body,”	says	 Zakhari.	“This	is	cutting	edge	research	with	 broad	implications	and	the	University	of		 Colorado	is	playing	an	important	role.”
Lisa Marshall is a freelance writer who specializes in health, sustainable living and outdoor adventure.

Dr. Anderson Receives $1.5 Million in Supplemental Funds from NIH
Associate professor, Peter Anderson, PharmD,	recently	received	notification	that	research	he	is	conducting	on	the	use	of	daily,	oral	antiretroviral	drugs	 prior	to	exposure	to	HIV	has	been	awarded	$1.5	million	in	supplemental	funds	from	the	National	Institutes	of	Health.	These	funds	are	in	addition	to	the	 4-year	research	grant	he	already	received.	His	work	was	highlighted	in	the	November	edition	of	the New England Journal of Medicine.

Summer 2011

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Pharmacy Perspectives - Fall 2011

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