Rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene are defining events in several tumors, including Anaplastic Large Cell Lymphoma (ALCL) and Non-Small Cell Lung Carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared to other types of T cell lymphoma or EGFR and K-RAS mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC we found that under hypoxic conditions ALK directly regulated the abundance of Hypoxia-Inducible Factors (HIFs), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF-1α and HIF-2α in hypoxic conditions required ALK activity and its downstream signaling proteins Stat3 and C/EBPβ. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF-2α, but not HIF-1α, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF-1α and HIF-2α. In conclusion, we uncovered an ALK specific regulation of the hypoxia response across different ALK positive tumor types, and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC.

Activation of the oncogene AEG-1 (MTDH, LYRIC) has been implicated recently in the development of hepatocellular carcinoma (HCC). In mice, HCC can be initiated by exposure to the carcinogen DEN, which has been shown to rely upon activation of NF-κB in liver macrophages. Because AEG-1 is an essential component of NF-κB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1–deficient mice displayed resistance to DEN-induced HCC and lung metastasis. No difference was observed in the response to growth factor signaling or activation of AKT, ERK, and β-catenin, compared with wild-type control animals. However, AEG-1–deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation. Mechanistic investigations showed that IL6 production and STAT3 activation, two key mediators of HCC development, were also deficient along with other biologic and epigenetics findings in the tumor microenvironment, confirming that AEG-1 supports an NF-κB–mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-κB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development. Cancer Res; 74(21); 1–10. ©2014 AACR.

Activation of the oncogene AEG-1 (MTDH, LYRIC) has been implicated recently in the development of hepatocellular carcinoma (HCC). In mice, HCC can be initiated by exposure to the carcinogen DEN, which has been shown to rely upon activation of NF-kB in liver macrophages. Since AEG-1 is an essential component of NF-kB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1-deficient mice displayed resistance to DEN-induced HCC and lung metastasis. No difference was observed in the response to growth factor signaling or activation of Akt, ERK and B-catenin, compared to wild-type control animals. However, AEG-1-deficient hepatocytes and macrophages exhibited a relative defect in NF-kB activation. Mechanistic investigations showed that IL-6 production and STAT-3 activation, two key mediators of HCC development, were also deficient along with other biological and epigenetics findings in the tumor microenvironment confirming that AEG-1 supports an NF-kB-mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-kB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development.

Each year, more than 1.2 million new patients are diagnosed with cancer every year in the United States.

To help combat this, Stand Up 2 Cancer brings together dream teams of the best and the brightest researchers spanning disciplines, institutions, countries and specialties, to join in a unified fight against cancer with translational research.

By providing these teams with long term funding, groups of scientists from peer institutions get to work collaboratively, rather than competitively, to develop new treatments quickly.

Transforming Pancreatic Cancer to a Treatable Disease

Over the next three years, the newly announced SU2C-Lustgarten Foundation Pancreatic Cancer Convergence dream team hopes to apply advances in immunotherapy (hardwiring the body’s immune system to fend off cancer as opposed to more traditional treatment options) to the realm of pancreatic cancer.

Co-leading the effort is Penn Medicine’s own director of Translational Research, Robert Vonderheide, MD, DPhil.

Why Pancreatic Cancer?

As the fourth leading cause of cancer death in the United States, pancreatic cancer remains one of the most deadly. Despite recent advancements, survival rates remain poor, as more than 90 percent of pancreatic cancer patients die within the first year of diagnosis, creating an urgent need for new treatments.

Why Immunotherapy?

Clinical efforts focused specifically on pancreatic cancer have failed to improve the survivability or quality of life for those affected. In short, greater research and better answers must be created or found, through novel approaches like immunotherapy.

Today, those diagnosed with the cancer, their caretakers and loved ones face a grim prognosis. To help alleviate this need in the pancreatic cancer community, Stand Up 2 Cancer is bringing together researchers, scientists, and doctors from institutions across the country to work together.

Each year, more than 1.2 million new patients are diagnosed with cancer every year in the United States.

To help combat this, Stand Up 2 Cancer brings together dream teams of the best and the brightest researchers spanning disciplines, institutions, countries and specialties, to join in a unified fight against cancer with translational research.

By providing these teams with long term funding, groups of scientists from peer institutions get to work collaboratively, rather than competitively, to develop new treatments quickly.

Transforming Pancreatic Cancer to a Treatable Disease

Over the next three years, the newly announced SU2C-Lustgarten Foundation Pancreatic Cancer Convergence dream team hopes to apply advances in immunotherapy (hardwiring the body’s immune system to fend off cancer as opposed to more traditional treatment options) to the realm of pancreatic cancer.

Co-leading the effort is Penn Medicine’s own director of Translational Research, Robert Vonderheide, MD, DPhil.

Why Pancreatic Cancer?

As the fourth leading cause of cancer death in the United States, pancreatic cancer remains one of the most deadly. Despite recent advancements, survival rates remain poor, as more than 90 percent of pancreatic cancer patients die within the first year of diagnosis, creating an urgent need for new treatments.

Why Immunotherapy?

Clinical efforts focused specifically on pancreatic cancer have failed to improve the survivability or quality of life for those affected. In short, greater research and better answers must be created or found, through novel approaches like immunotherapy.

Today, those diagnosed with the cancer, their caretakers and loved ones face a grim prognosis. To help alleviate this need in the pancreatic cancer community, Stand Up 2 Cancer is bringing together researchers, scientists, and doctors from institutions across the country to work together.