The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti–HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody. Cancer Res; 75(1); 1–12. ©2014 AACR.

The anti-HER receptor antibodies cetuximab, trastuzumab and pertuzumab are used widely clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, is emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3 and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti-HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody.

You’ve probably seen them out and about: ads for electronic, or “E” cigarettes that say they are an alternative to traditional tobacco products. But are they safer? Do they pose other risks?

We sat with Frank Leone, MD, MS, Director, Comprehensive Smoking Treatment Programs at Penn Medicine to talk about the trend in e-cigarettes.

What are e-cigarettes?

E-cigarettes as a class have been around for about 10 years, though individual brands have not been around that long. They are battery-powered devices that simulate tobacco smoking. An internal heating element vaporizes a liquid solution, which is inhaled and exhaled. Some vapor solutions contain a flavored solution, others have added nicotine in various concentrations.

It sounds safer than tobacco, is it?

In the short term, it probably isn’t that bad. Think about it. When you go see a theater performance, or a band perform, you might be exposed to “smoke” from a smoke machine. That smoke machine is using the same, or similar vapor as e-cigarettes. The vapor in e-cigarettes contains propylene glycol, a substance that is probably not best inhaled over long periods of time.

Short term effects of that smoke machine in a theater are probably okay, but what about the next 10, 15, 20 or 30 years? It might not accumulate in the lungs, but maybe the bladder or liver. It might do different harm than regular cigarettes.

Can e-cigarettes help people quit smoking?

E-cigarettes have the potential to be an effective alternative, if they really help people stop smoking. The problem is, it’s not really a guaranteed way to quit smoking entirely. For many, it’s simply substituting one smoking behavior for another.

In fact, in a recent study, researchers found that teens who used e-cigarettes were more likely to smoke real cigarettes, and less likely to quit than those that never used e-cigarettes.

Nicotine addiction is complex. People addicted to nicotine know it’s bad for them, yet they can’t stop. And those not addicted to nicotine can’t understand why smokers can’t quit. Even family members and friends have a hard time understanding nicotine addiction.

Quit Smoking with Penn

Penn Medicine’s Comprehensive Smoking Treatment Program works hard to help smokers and their families understand why they feel trapped and powerless to change. Our team tries to understand the specific needs of every smoker, whether it relates to health, family, work, or other aspects of their lives.

Our program is based on the belief that smokers deserve to quit comfortably, so the treatment tends to be aggressive with medications in a way that helps keep that “devil inside” quiet. Most of all, the team respects the problem for what it is, an addiction. And they respect the people struggling to find a way out from under it.

Specialists in Penn’s Comprehensive Smoking Treatment Program have been fortunate to help thousands of patients overcome nicotine addiction over the years, and it’s amazingly rewarding. Patients keep in touch with the program throughout the years. Our staff answers their questions, provides them with support during difficult times, and helps them to get right back on track if they relapse.

You’ve probably seen them out and about: ads for electronic, or “E” cigarettes that say they are an alternative to traditional tobacco products. But are they safer? Do they pose other risks?

We sat with Frank Leone, MD, MS, Director, Comprehensive Smoking Treatment Programs at Penn Medicine to talk about the trend in e-cigarettes.

What are e-cigarettes?

E-cigarettes as a class have been around for about 10 years, though individual brands have not been around that long. They are battery-powered devices that simulate tobacco smoking. An internal heating element vaporizes a liquid solution, which is inhaled and exhaled. Some vapor solutions contain a flavored solution, others have added nicotine in various concentrations.

It sounds safer than tobacco, is it?

In the short term, it probably isn’t that bad. Think about it. When you go see a theater performance, or a band perform, you might be exposed to “smoke” from a smoke machine. That smoke machine is using the same, or similar vapor as e-cigarettes. The vapor in e-cigarettes contains propylene glycol, a substance that is probably not best inhaled over long periods of time.

Short term effects of that smoke machine in a theater are probably okay, but what about the next 10, 15, 20 or 30 years? It might not accumulate in the lungs, but maybe the bladder or liver. It might do different harm than regular cigarettes.

Can e-cigarettes help people quit smoking?

E-cigarettes have the potential to be an effective alternative, if they really help people stop smoking. The problem is, it’s not really a guaranteed way to quit smoking entirely. For many, it’s simply substituting one smoking behavior for another.

In fact, in a recent study, researchers found that teens who used e-cigarettes were more likely to smoke real cigarettes, and less likely to quit than those that never used e-cigarettes.

Nicotine addiction is complex. People addicted to nicotine know it’s bad for them, yet they can’t stop. And those not addicted to nicotine can’t understand why smokers can’t quit. Even family members and friends have a hard time understanding nicotine addiction.

Quit Smoking with Penn

Penn Medicine’s Comprehensive Smoking Treatment Program works hard to help smokers and their families understand why they feel trapped and powerless to change. Our team tries to understand the specific needs of every smoker, whether it relates to health, family, work, or other aspects of their lives.

Our program is based on the belief that smokers deserve to quit comfortably, so the treatment tends to be aggressive with medications in a way that helps keep that “devil inside” quiet. Most of all, the team respects the problem for what it is, an addiction. And they respect the people struggling to find a way out from under it.

Specialists in Penn’s Comprehensive Smoking Treatment Program have been fortunate to help thousands of patients overcome nicotine addiction over the years, and it’s amazingly rewarding. Patients keep in touch with the program throughout the years. Our staff answers their questions, provides them with support during difficult times, and helps them to get right back on track if they relapse.

Cancer stem cells (CSC) are thought to play a major role in the development and metastatic progression of pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Likewise, the tumor microenvironment contributes critical support in this setting, including from tumor stromal cells and tumor-associated macrophages (TAM) that contribute structural and paracrine-mediated supports, respectively. Here, we show that TAMs secrete the IFN-stimulated factor ISG15, which enhances CSC phenotypes in PDAC in vitro and in vivo. ISG15 was preferentially and highly expressed by TAM present in primary PDAC tumors resected from patients. ISG15 was secreted by macrophages in response to secretion of IFNβ by CSC, thereby reinforcing CSC self-renewal, invasive capacity, and tumorigenic potential. Overall, our work demonstrates that ISG15 is a previously unrecognized support factor for CSC in the PDAC microenvironment with a key role in pathogenesis and progression. Cancer Res; 74(24); 1–12. ©2014 AACR.