Despite its function as an inhibitor of urokinase and tissue-type plasminogen activator (PA), PA inhibitor-1 (PAI-1) has a paradoxical protumorigenic role in cancer, promoting angiogenesis and tumor cell survival. In this review, we summarize preclinical evidence in support of the protumorigenic function of PAI-1 that has led to the testing of small-molecule PAI-1 inhibitors, initially developed as antithrombotic agents, in animal models of cancer. The review discusses the challenges and the opportunities that lay ahead to the development of efficacious and nontoxic PAI-1 inhibitors as anticancer agents. Cancer Res; 75(15); 1–6. ©2015 AACR.

Preclinical models often fail to capture the diverse heterogeneity of human malignancies and as such lack clinical predictive power. Patient-derived tumor xenografts (PDX) have emerged as a powerful technology: capable of retaining the molecular heterogeneity of their originating sample. However, heterogeneity within a tumor is governed by both cell-autonomous (e.g., genetic and epigenetic heterogeneity) and non–cell-autonomous (e.g., stromal heterogeneity) drivers. Although PDXs can largely recapitulate the polygenomic architecture of human tumors, they do not fully account for heterogeneity in the tumor microenvironment. Hence, these models have substantial utility in basic and translational research in cancer biology; however, study of stromal or immune drivers of malignant progression may be limited. Similarly, PDX models offer the ability to conduct patient-specific in vivo and ex vivo drug screens, but stromal contributions to treatment responses may be under-represented. This review discusses the sources and consequences of intratumor heterogeneity and how these are recapitulated in the PDX model. Limitations of the current generation of PDXs are discussed and strategies to improve several aspects of the model with respect to preserving heterogeneity are proposed. Cancer Res; 75(15); 1–6. ©2015 AACR.

Hairy cell leukemia (HCL) is characterized by under-expression of the intracellular signaling molecule RhoH. Reconstitution of RhoH expression limits HCL pathogenesis in a mouse model indicating this could represent a new therapeutic strategy. However, while RhoH reconstitution is theoretically possible as a therapy, it is technically immensely challenging as RhoH protein that is appropriately functional needs to be specifically targeted. Because of this problem, we sought to identify druggable proteins on the HCL surface that were dependent upon RhoH under-expression. One such protein was identified as CD38. Analysis of 51 HCL patients, demonstrated that 18 were CD38-positive. Interrogation of the clinical record of 23 relapsed HCL patients demonstrated those that were CD38-positive had a mean time to salvage therapy 71 months shorter than patients who were CD38-negative. Knockout of the CD38 gene in HCL cells increased apoptosis, inhibited adherence to endothelial monolayers and compromised ability to produce tumors in vivo. Furthermore, an anti-CD38 antibody proved effective against pre-existing HCL tumors. Taken together, our data indicate that CD38 expression in HCL drives poor prognosis by promoting survival and heterotypic adhesion. Our data also indicate that CD38-positive HCL patients might benefit from treatments based on CD38 targeting.

Since President Barack Obama’s State of the Union Address in January 2015, the nation has been talking about a revolution in patient care, known by many as precision medicine.

Of course, the country is used to hearing the president talk about health care, especially the Affordable Care Act. But when the White House starts launching $215 million initiatives to accelerate research—in this case, the Precision Medicine Initiative, according to a White House Press release—you can be sure it’s not just a passing fad.

First, what is precision medicine?

Precision medicine is about tailoring treatments to the patient’s genome and body function. The promise is that this detailed personal health data can determine what’s most effective for each individual, which can lead to better outcomes.

Most of precision medicine’s application currently focuses on cancer. Launched in 2013, Penn Medicine’s Center for Personalized Diagnostics (CPD) helps oncologists determine the best treatment for their cancer patients by looking at the cancer’s genome.

Here’s how precision medicine is being practiced at Penn:

1. A patient is diagnosed with cancer.
2. If the cancer involves a solid tumor—like breast, lung, or colon cancer—the tumor is surgically removed during a biopsy, and a chunk of the tissue is sent to Penn Medicine’s CPD. If the cancer involves blood or bone marrow—like leukemia—a sample of the blood or bone marrow is sent.
3. The CPD sequences a panel of genes that are known to be involved in cancer. This test examines DNA within the tumor, blood or bone marrow sample. The goal is to find DNA mutations that are driving the cancer.
4. A report on the mutations found is sent to the patient’s oncologist.
5. The oncologist determines if there are therapies or treatments available that work better than others—or not at all—on the patient’s particular type of cancer.

“We’re using precision medicine to give patients the right drugs, guided by the DNA sequence information from their cancer, so we’re not exposing them to potentially toxic effects,” explains David Roth, MD, PhD, director of the CPD. “This individualized therapy is better than treatment based on the ‘average patient.’”

Precision Medicine is being researched, translated and applied across Penn Medicine. Here,
experts from the Center for Personalized Diagnostics share four predictions on how precision medicine will change how cancer is treated in future generations.

1. Cancer will be diagnosed earlier.

Jennifer Morrissette, PhD, clinical director of the CPD:

“There are different stages of tumors. The earlier you catch the tumor, the more likely you are to survive it. My theory is that this century will be the century of diagnostics. We will be diagnosing people’s cancers earlier and earlier.

“That way, we are not dealing with advanced metastatic tumors that have acquired so many different changes that they’re hard to treat. We’ll be capturing tumors very early, in stage one; have a definitive surgery; follow the patient for a certain number of years to make sure that the cancer hasn’t spread; and then they’ll be cured.

“Some people put off seeing a physician because they don’t want chemo, but the longer they put it off, the more likely they are going to have metastatic disease.”

2. Cancer treatment will be based on each person’s health profile.

David Roth, MD, PhD, director of the CPD:

“[In the past,] doctors had been treating [the average patient] based upon results from a large study.

“The revolution in precision medicine is that now we have better tools to understand what’s going on with you as an individual. Instead of saying, ‘Okay, you have this particular cancer, and you have a 30 percent chance. So, go ahead and get this toxic therapy,’ we can be much more specific.

“If we were able to tell you that you have a five percent chance of responding to a chemotherapy based on the makeup of your tumor, would you still do it?”

3. Gene paneling will be used for diagnosis, not just treatment.

David Lieberman, MS, CGC (certified genetic counselor):

“We tend to see certain genes mutated in certain cancers. For example, there is a certain set of
genes [that are] typically mutated in lung cancer or another set in lymphoma.

“It is not always clear using historical methods what type of cancer a patient has. This makes treatment decisions challenging. Sequencing the tumor’s DNA on a panel of known cancer-related genes may help clarify the cancer’s origin and, in this way, assist the clinician in determining treatment or prognosis.”

$215 million: The amount the White House will invest in the Precision Medicine Initiative in 2016
Source: WhiteHouse.gov

4. More cancer patients will have a treatment team, rather than just an       oncologist.

Jennifer Morrissette PhD, clinical director of the CPD:

“It’s not going to be one physician making all the decisions. Cancer treatment has gotten much more complex. Because of the availability of multi-gene testing, you need a group of people with different types of expertise to make the best decision for a patient.

“In addition to the team directing care for the appropriate approach—whether it’s surgery, radiation, chemotherapy, pain management—now there is also the genetic component.

“[The team’s] able to sit in a room with people from the lab who can talk about what the result means, have the oncologist tell them about the patient and then get the clinical geneticist’s notion that there may be an inherited predisposition. Then, they walk out with a consolidated treatment plan for that patient.”

The future of medicine

For more than 250 years, advancements like “precision medicine” have been the hallmark of Penn Medicine. As the first school of medicine in the United States, it has been and continues to be a place where the future of medicine and the future leaders in medicine are being developed.

Interested in learning more about precision medicine? Please contact Karen Kreeger

Combining cell-cycle checkpoint kinase inhibitors with the DNA-damaging chemotherapeutic agent gemcitabine offers clinical appeal, with a mechanistic rationale based chiefly on abrogation of gemcitabine-induced G2–M checkpoint activation. However, evidence supporting this mechanistic rationale from chemosensitization studies has not been consistent. Here we report a systematic definition of how pancreatic cancer cells harboring mutant p53 respond to this combination therapy, by combining mathematical models with large-scale quantitative biologic analyses of single cells and cell populations. Notably, we uncovered a dynamic range of mechanistic effects at different ratios of gemcitabine and CHK1 inhibitors. Remarkably, effective synergy was attained even where cells exhibited an apparently functional G2–M surveillance mechanism, as exemplified by a lack of both overt premature CDK1 activation and S-phase mitotic entry. Consistent with these findings, S–G2 duration was extended in treated cells, leading to a definable set of lineage-dependent catastrophic fates. At synergistic drug concentrations, global replication stress was a distinct indicator of chemosensitization as characterized molecularly by an accumulation of S-phase cells with high levels of hyperphosphorylated RPA-loaded single-stranded DNA. In a fraction of these cells, persistent genomic damage was observed, including chromosomal fragmentation with a loss of centromeric regions that prevented proper kinetochore-microtubule attachment. Together, our results suggested a “foot-in-the-door” mechanism for drug synergy where cells were destroyed not by frank G2–M phase abrogation but rather by initiating a cumulative genotoxicity that deregulated DNA synthesis. Cancer Res; 75(17); 1–13. ©2015 AACR.