Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non–small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis. Cancer Res; 74(12); 1–12. ©2014 AACR.

Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed 13C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation. Cancer Res; 74(12); 1–15. ©2014 AACR.

Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in colorectal cancer cell lines closely resembled those seen in primary colorectal tumors. Similarities included the presence of two hypermutation phenotypes, as defined by signatures for defective DNA mismatch repair and DNA polymerase ε proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFβ, and p53 pathways. Furthermore, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, and SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, and TRRAP). Chromosomal instability was prevalent in nonhypermutated cases, with similar patterns of chromosomal gains and losses. Although paired cell lines derived from the same tumor exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differences mainly reflected a preexisting heterogeneity in the tumor cells. In conclusion, our results establish that human colorectal cancer lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate colorectal cancer biology and drug responses. Cancer Res; 74(12); 1–10. ©2014 AACR.

In 2011, Bill Barbour was diagnosed with prostate cancer and treated with proton therapy at Penn Medicine. Today, he is cancer free.

But this story isn’t about Bill.

An avid cyclist, Bill is riding the inaugural Ride to Conquer Cancer Philadelphia ride this October.

Though he’s not doing it for himself.

“For many people participating, the ride is a metaphor for their life and their survival,” says Bill. “The ride has a purpose, beginning, support, family, friends, challenges and a finish. It may be analogous to someone’s journey through their cancer battle,” Bill adds.

But for Bill, the ride is about possibilities – and how dollars earned through the ride directly contribute to life-saving cancer research at the Abramson Cancer Center.

“I believe in the research happening at Penn,” says Bill who is most recently inspired by the story of Emma Whitehead who is cancer-free because of Dr. Carl June’s cancer research at the Abramson Cancer Center. “The research happening today will create new therapies to save lives tomorrow. I want to support that.”

Bill says the opportunity to help raise money for cancer research brings to mind an impressive scene from the 2001 movie, Gladiator.

Bill describes Russell Crowe’s character as the Roman general that is preparing his men to enter battle. The general looks around to the men who will ultimately give their lives for the fight he proclaims, “Brothers, what we do in life echoes in eternity!”

Bill says that “we can make such echoes in our support of cancer research today that will benefit generations to come.”

Visit Bill’s online fundraising page here. 

The Ride to Conquer Cancer©

Join Penn Medicine’s Abramson Cancer Center (ACC) on October 11 to 12, 2014 in the Ride to Conquer Cancer© (RTCC)—an unforgettable and epic bike ride through Pennsylvania’s picturesque scenery -towards one life-changing destination: to cure cancer. The ride isn’t just for cyclists, it’s for anyone who wants to see a cure for cancer.

At two-days and 150+ miles the RTCC will be a physical challenge—and an emotional and inspirational weekend—that will give you a chance to join forces with our physicians, patients, and families to leave everything on the bike course and raise serious funds and awareness in the ACC’s fight to cure cancer.

The funds raised through the ride will be put to use immediately, powering the ACC’s vision to eradicate cancer as a cause of human disease and suffering through precision medicine, novel research, next-generation therapies, and compassionate care.

JOIN TODAY!

This event will be remarkable and will bring together communities of cancer survivors, cyclists, and their supporters with a common goal to conquer this disease. Join the ride in October by registering today at www.ridetovictory.org or by calling (844) 777-7433.

Before the ride, you will have access to:

• Expert coaching
• Training rides in your area
• Personal web page for fundraising
• Helpful manual
• 2014 ride commemorative item

During the ride, participants will have access to:

• Support along the route
• Catered meals
• Entertainment at camp
• Massage and medical care