Lynda Seminara

Research by Jeremy Chien, PhD, of the Cancer Biology Program at The University of Kansas may hasten the effort to determine which strains of cancer will eventually become resistant to chemotherapy, paving the way for developing more effective targeted treatments.

With grants from the Department of Defense and the American Cancer Society, Chien and his team are striving to find the genes responsible for resistance to chemotherapy.

Their innovative system was inspired by early investigations into cancer genomics.

&lsquo;Functional genomics&rsquo; was pioneered in the 1980s by Robert A. Weinberg, PhD, who discovered the first human oncogenea gene that can cause normal cells to form cancerous tumors.

Weinberg et al used genomic DNA, which contains the entire genetic code for a cell that is passed from one generation to the next from tumor cells and infected murine fibroblast 3T3 cells.

The fact that these 3T3 cells can reproduce indefinitely without initiating tumor growth helped Weinberg determine which genes are responsible for the cancer-causing abnormal cell growth.

Chien et al are applying this premise but drawing from a larger pool of genetic information.

Using ten tumor samples from patients with chemo-resistant ovarian cancer, they are extracting mRNA, which carries the blueprint of a protein from the cell&rsquo;s DNA to its ribosomes that drive protein production.

, Chien said that their current emphasis is on ovarian cancer &ldquo;because it is a prototypical disease for p53 dysfunction. We are currently focusing on TP53 mutations because TP53 is estimated to be mutated in over 50% of human cancer. So, drugs that exploit TP53 defects are expected to impact several cancer types where TP53 is mutated.&rdquo;&nbsp;Hence, their findings may have wide-ranging implications. &nbsp;

The mRNA from the tumor samples will be converted into cDNA, which is the opposite of what normally occurs (RNA is formed from DNA).

Chien is using the reverse transcription process because he &ldquo;wants to express a specific protein in a cell that does not normally express in that protein.&rdquo;

The new cDNA is placed in a cDNA expressing library.

Here, the cDNA is put into host cells, and &ldquo;all together they contain the RNA from the original tumor samples.&rdquo;

Aptly, Chien calls this a &ldquo;genome-wide cancer toolkit.&rdquo;

He said that the kit can be used to identify cancer genes that cause the transformed phenotype, that promote metastatic phenotypes, or that cause resistance to drug treatment.

The team&rsquo;s current focus is drug resistance, so they are searching for the appropriate phenotype.

Once the DNA library has been created, Chien et al will introduce the cDNA into an ovarian cancer cell that is normally sensitive to chemotherapy.

They plan to test two types of chemotherapy commonly used for ovarian cancer: carboplatin and taxol.

Cells that demonstrate resistance to treatment will be extracted, and the gene within can be sequenced and identified as being chemo-resistant.

Once the genes responsible for chemo-resistance have been identified, Chien and his team will test current and new drugs aimed at targeting the culprit genes, giving hope to patients who cannot be treated successfully with standard therapies.

He is already enthused about potential treatment options for a candidate gene in the toolkit that &ldquo;may play a role in taxol resistance, which happens to have a drug that can inhibit that gene,&rdquo; he said. He also added that &ldquo;It&rsquo;s already out there being used to treat another disease; it just hasn&rsquo;t yet been tested in treating ovarian cancer.&rdquo;

He noted that if a drug exists to combat the candidate genes, &ldquo;we will start using it to treat cancer. Otherwise, we will develop new drugs to target them.&rdquo;

Identifying these genes is a critical step in targeting them to reverse chemotherapy resistance or to make chemotherapy more effective, said Chien.

&ldquo;As we move toward precision cancer medicine, there is an increasing emphasis on genetically based clinical trials that exploit genetic vulnerabilities and oncogene addiction in cancer for therapeutic benefits,&rdquo; explained Chien in the interview. &ldquo;At a fundamental level, we are looking to understand the genetic basis for chemotherapy resistance, and [gain] better understanding of tumor-intrinsic genetic factors that contribute to chemotherapy resistance. This will allow us to develop targeted therapies that restore sensitivity to chemotherapy or extend the durability of current chemotherapies,&rdquo; he said.

A future goal for Chien&rsquo;s research program is to develop &ldquo;rational combinations of cancer therapies that exploit genetic defects and harness the power of the immune system with immunotherapies,&rdquo; said Chien. His team plans to investigate drugs that target biological pathways activated by TP53 that also have the ability to enhance tumor immunity.

1. &nbsp;&nbsp; The University of Kansas Cancer Center. Rewriting the book on chemo-resistant cancers with a DNA library [press release]. http://www.newswise.com/articles/view/635003/?sc=mwhr&xy=10013055. Accessed July 10, 2015.

2. &nbsp;&nbsp; MIT Whitehead Institute. Faculty information: Robert A. Weinberg. http://wi.mit.edu/people/faculty/weinberg. Accessed July 11, 2015.

3. &nbsp;&nbsp; McCoy MS, Toole JJ, Cunningham JM, Change EH, Lowy DR, Weinberg RA. Characterization of a human colon/lung carcinoma oncogene.

Articles

Research may hasten the effort to determine which strains of cancer will eventually become resistant to chemotherapy, paving the way for developing more effective targeted treatments.

New Research to Identify Chemo-Resistant Genes in Ovarian Cancer

A study, by M. Cecilia Cano, PhD, et al at the Wistar Institute, Philadelphia, has shown that monotherapy treatment with phosphatidylinositol-3 kinase (PI3K) inhibitors may worsen a patient&rsquo;s cancer by causing more aggressive tumor cell behavior and increasing the likelihood of metastases to other organs.

According to these findings, published in

Proceedings of the National Academy of Sciences

PI3K inhibitors appear to reprogram tumor cell mitochondria and move them to positions that promote the spread of disease.

PI3K inhibitors function by impeding one or more of the PI3K enzymes of the PI3K/AKT/mTOR pathwayan important signaling pathway for many cellular functions, including growth control, metabolism, survival, and proliferation.

This pathway contains numerous components, the inhibition of which may result in tumor suppression.

Therefore, PI3K has been deemed a master switch by many cancer researchers

and has become the focus of extensive research on therapies aimed at targeting every aspect of the pathway.

Despite the initial promise of these medicines, PI3K inhibitors have produced only modest short-term benefits, perhaps due to drug resistance.

Drug resistance is a key barrier in achieving long-term remission, or even cures, and considerable effort is being devoted to better understanding how tumors adapt to therapy, how tumors maintain metastatic potential, and how they continue growing.

Some tumors may adaptively reprogram their signaling pathways to evade therapy-induced stress, in turn acquiring more aggressive disease traits.

Dario C. Altieri, MD, president and CEO of the Wistar Institute and the lead study investigator, stated that small-molecule inhibitors of PI3K should not be used as monotherapy. &ldquo;Our research has shown that tumors quickly adapt to this regimen and acquire traits of a more aggressive and potentially invasive disease,&rdquo; he said. However, these agents may be beneficial for combination regimens.

Altieri et al focused on the role of the mitochondrion, which is the portion of the cell responsible for energy production. Specifically, the researchers sought to discern how mitochondria become reprogrammed when exposed to PI3K inhibition and how these energy sources may prevent the effectiveness of targeted agents from reaching expectations.

PI3K inhibition caused mitochondria to migrate to the peripheral cytoskeleton of the tumor cells, whereas the mitochondria of untreated cells were seen clustered around the cell nucleus. PI3K inhibition diverted the mitochondria to specialized regions of the cell membrane that are implicated in cell motility, and thus, the cells could move spontaneously, permitting invasion.

Earlier work by Altieri et al confirmed that tumor cells rely on the energy produced by mitochondria more significantly than previously thought; however, &ldquo;What we have shown in this [new] study is that, in somewhat of a paradox, treatment with a PI3K inhibitor causes a tumor cell&rsquo;s mitochondria to produce energy in a localized manner, promoting a far more aggressive and invasive phenotype,&rdquo; Altieri said.

Therefore, he feels that this treatment appears to be &ldquo;doing the opposite of its intended effect.&rdquo;

Regardless, Altieri noted,  &ldquo;These findings continue to support the idea that the mitochondria of tumor cells are crucial to tumor survival and proliferation. It&rsquo;s certainly counterintuitive that a drug designed to fight cancer may in actuality help it spread, but by identifying why this is happening, we can develop better strategies that allow these drugs to treat tumors the way they should.&rdquo;

These findings emphasize the need for greater understanding of how molecular therapy may affect tumor behavior, according to Altieri. &ldquo;Mechanisms of cellular adaptation like the one described in our study may be directly responsible for treatment failure [observed] in the clinic.&rdquo;

Altieri affirmed that mitochondrial function plays a key role in the adaptation of tumors to PI3K therapy. In turn, &ldquo;this promotes a more invasive phenotype,&rdquo; he said, which leads to new research opportunities. &ldquo;It is now feasible to target mitochondria for cancer therapy, and we envision new studies to&nbsp;focus on rational combination strategies to interfere with mitochondrial adaptation together with PI3K inhibition,&rdquo; he stated. Altieri and his team have shown that targeting mitochondrial functions for tumor therapy is feasible, and it could eventually represent a novel therapeutic strategy.

Caino MC, Ghosh JC, Chae YC, et al. PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion.

2015; Jun 29. doi: 10.1073/pnas.1500722112.

The Wistar Institute. Despite being designed to treat cancer, this class of drugs appears to reprogram the mitochondria of tumor cells and move them to &ldquo;strategic&rdquo; positions for invasion [press release]. http://www.newswise.com/articles/view/636357/?sc=sphr&xy=10013055. Accessed July 2, 2015.

Kurtz JE, Ray-Coquard I. PI3 kinase inhibitors in the clinic: an update.

Akinleye A, Avvaru P, Furqan M, Song Y, Liu D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics.

2013;6(1):88. doi: 10.1186/1756-8722-6-88.

American Society of Clinical Oncology. Exploring the pathway: the PI3K pathway fact sheet. 2015; May 31. http:// https://am.asco.org/exploring-pathway-pi3k-pathway-fact-sheet. Accessed July 2, 2015.

Proceedings of the National Academy of Sciences of the United States of America. PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion [Significance]. http://www.pnas.org/content/early/2015/06/23/1500722112.abstract. Accessed July 2, 2015.

A study, by M. Cecilia Cano, PhD, et al at the Wistar Institute, Philadelphia, has shown that monotherapy treatment with PI3K inhibitors may worsen a patientâ€™s cancer by causing more aggressive tumor cell behavior and increasing the likelihood of metastases to other organs.

PI3K Inhibition May Fuel Cancer Rather Than Fight It

Inhibition of the activin receptor-like kinase 1 (ALK1) protein may prevent metastasis of breast cancer,

. Kristian Pietras, PhD et al at Lund University in Sweden found that metastasis was more common in patients with breast cancer who have high levels of ALK1 protein in their tumor blood vessels.

Therefore, inhibition of the ALK1 pathway may be beneficial in the treatment of metastatic disease.

ALK1, a receptor of the transforming growth factor-beta (TGF-&szlig;) family, is selectively expressed on activated endothelial cells. ALK1 promotes vascular maturation and stabilization, angiogenesis steps that follow those regulated by vascular endothelial growth factor (VEGF).

Pietras stated that greater knowledge of the metastatic process, coupled with efforts to minimize disease spread, is essential for effective clinical management.

&ldquo;We are investigating the role of ALK1 protein expressed by endothelial cells in promoting metastatic dissemination from primary breast tumors,&rdquo; Pietras said.

He explained that the spread of cancer involves a host of cell activity: a cancer cell must detach and transverse the vascular wall to escape into the bloodstream, then must exit the vasculature to enter the metastatic site, and colonize the new tissue.

Because the process of escape into and from the vasculature is

it may be possible to use drugs to block this process.

In their study aimed at understanding the role of ALK1 in breast cancer metastasis, Pietras and his team examined murine models of breast cancer; tumor samples from patients in a population-based, nested case-control study; and breast cancer gene-expression data. They also tested an ALK1 inhibitor, dalantercept.

Dalantercept is a first-in-class angiogenesis inhibitor whose mechanism of action is distinct from that of VEGF inhibition.

This investigational agent acts by preventing BMP9 and BMP10 (proteins of the TGF-&szlig; superfamily) from interacting with ALK1.

Dalantercept is being developed specifically for the treatment of patients with advanced cancer for whom other treatment has failed.

The authors found that a mouse version of dalantercept prevented metastatic dissemination, and that combination treatment with chemotherapy (docetaxel + dalantercept) stopped the spread of primary breast tumor to the lungs.

Analysis of gene-expression patterns in tumors from 768 patients revealed a significant association between ALK1 expression and the incidence of metastatic disease.

Similarly, gene-expression data from The Cancer Genome Atlas showed that ALK1 expression correlates with the expression of well-known endothelial markers, and that higher levels of ALK1 expression are an independent prognostic indicator of poor survival among patients with breast cancer.

Targeting ALK1 has become a popular anticancer research endeavor, and preclinical studies have shown promising results.

Dalantercept has produced potent antitumor activity and decreased tumor vascularity in a variety of preclinical models.

In a clinical study of 37 patients with advanced solid tumors, dalantercept monotherapy produced antitumor activity but not without side effects, which included fatigue, peripheral edema, and anemia.

Other adverse events, observed in patients with advanced renal cell carcinoma (RCC), include diarrhea, nausea, dysphonia, decreased appetite, hypertension, and arthralgia.

Earlier this year, the combination of dalantercept and axitinib (a small-molecule tyrosine kinase inhibitor) was administered in humans, yielding favorable antitumor response in seven of 28 patients with advanced RCC, and disease stabilization in 17 patients.

Breast Cancer Implications and Next Steps

Pietras said that their findings &ldquo;encourage clinical testing of drugs blocking ALK1 in breast cancer with prevention of metastatic dissemination as the primary outcome.&rdquo;

Moreover, further research is warranted to fully elucidate the safety profile of dalantercept in patients with breast cancer. Currently, Pietras and his team are conducting therapeutic studies of dalantercept in models of breast cancer to &ldquo;pinpoint the precise therapeutic regimen and disease stage at which the treatment is the most effective.&rdquo;

It is hoped that such knowledge will guide the tailoring of regimens that profoundly reduce metastasis and improve survival in humans.

American Association for Cancer Research. ALK1 protein may play a role in breast cancer metastasis [press release].

http://www.eurekalert.org/pub_releases/2015-06/aafc-apm061215.php

Angiogenesis-targeted combination active in advanced RCC.

http://www.targetedonc.com/articles/Angiogenesis-Targeted-Combination-Active-in-Advanced-RCC

Acceleron Pharma. Dalantercept product information.

http://www.acceleronpharma.com/products/dalantercept/

Cunha S, Pietras K. ALK1 as an emerging target for antiangiogenic therapy of cancer.

Mitchell D, Pobre EG, Mulivor AW, et al. ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth.

Cunha SI, Pardali E, Thorikay M, et al. Genetic and pharmacological targeting of activing receptor-like kinase 1 impairs tumor growth and angiogenesis.

Bendell JC, Gordon MS, Hurwitz HI, et al. Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept, an activing receptor-like kinase-1 ligand trap, in patients with advanced cancer.

Voss MH, Plimack ER, Rini BI, et al. The DART study part 2: a phase 2 randomized, double-blind study of dalantercept plus axitinib compared to placebo plus axitinib in patients with advanced renal cell carcinoma. Poster presented at: Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2015; Chicago, IL.

Inhibition of the activin receptor-like kinase 1 (ALK1) protein may prevent metastasis of breast cancer, according to a study published in Cancer Research.

Inhibiting ALK1 in Breast Cancer May Halt Metastases

US sales of targeted therapies to payers reached $10.4 billion by 2009 and remain on the rise.

May 18, 2015, aimed to determine trends in payer cost and use, as well as out-of-pocket (OOP) spending, for privately insured nonelderly patients receiving oral or intravenous (IV) chemotherapy for the treatment of cancer.

Medical oncologists have the benefit and burden of most treatment decisions, so it is important for them to understand the changing trends in costs and spending, according to one principal investigator of the study, Fabrice Smieliauskas, PhD who represented the study authors in an interview with

&ldquo;With so many new targeted therapies available for various cancers, patients and oncologists often have the benefit and the burden of choice, and should be prepared to discuss how drug costsboth total costs and patient OOP costs, which depend on oral or IV formulation and specific insurance benefits, might figure into their preferred treatment approach.&rdquo;

Data for three categories of drugs were examined in the study: targeted oral cancer medications (tOAMs), targeted IV cancer medications (tIVAMs), and an &ldquo;all others&rdquo; group.

The authors retrieved data from the LifeLink Health Plan Claims Database to study and disaggregate cost trends for 200,168 patients. (The database represents approximately 70 million patients and more than 80 health plans in the United States, and includes information on drug claims.) Data for cancer patients younger than age 65 who underwent chemotherapy during the study period (2001-2011) were reviewed for each month of the first year of treatment.

The average age of the study population was 52 years.

costs were extracted from the database for each patient.

denotes the amount billed to a health plan;

reflects the amount actually paid by the plan; and

is the amount permitted by the plan and includes the

amount plus any patient expenses such as copayments. OOP payments were calculated by subtracting

The authors documented cancer drug expenditures per patient per month (PPPM) and the overall first-year drug costs per patient, using paid values for payers and OOP data for patients. The PPPM amount was calculated as the sum of paid or OOP payments associated with the drug, divided by the months of exposure. Cost estimates were normalized to 2013 US dollars using the medical care component of the consumer price index. Statistical significance, defined as

<.05, was determined by CochranArmitage testing.

The authors used PPPM costs for the year in which each drug was approved by the US Food and Drug Administration as the proxy for launch price. To discern increases in cancer drug expenditures over time, the researchers considered: (1) increased use of higher-priced targeted therapies relative to nontargeted agents, (2) higher launch prices over time for newly approved targeted agents, and (3) price increases in targeted drugs following launch. To capture the impact of the growing availability of tOAMs since 2005, the increase in expenditures was determined and compared for two subperiods of the study: 2001 to 2005 and 2005 to 2010.

Monthly per-patient payments by insurance companies for tOAMs more than doubled during the study period, from $3381 PPPM in 2001 to $7370 in 2011 (

<.001), and surpassed those for tIVAMs by the final year. However, patient OOP spending for targeted oral agents was roughly half that of targeted IV therapies.

The latter trend &ldquo;is surprising and challenges conventional wisdom. This difference continues to grow as hospitals purchase physician practices, which increases billing rates and therefore OOP spending for administering targeted IV drugs. In this light, the push in many states to pass oral cancer drug parity legislation and to equalize patient financial burden for oral drugs with that of IV drugs may be misplaced,&rdquo; said Smieliauskas. &ldquo;Although the overall growth in cancer drug prices is well known, the dichotomy between more rapid increases in the total price of oral agents compared to IV agents, and lower OOP spending for oral agents, is important [for medical oncologists] to understand,&rdquo; Smieliauskas said.

Although OOP costs in the first year of chemotherapy were generally lower for the patients on targeted oral agents, payments for tOAMs grew substantially throughout the study period, from $642 PPPM in 2001 to $2124 in 2010.

The study also showed a large increase in the use of IV agents and a gradual climb in the use of oral agents. Targeted therapies accounted for a hefty 63% of all chemotherapy expenditures in 2011. Factors contributing to the growth in payer spending included increases in drug prices (both during and after launch) and the substitution of targeted therapies for cytotoxic and other agents.

Currently, targeted therapies dominate the spending for cancer treatments. Private payers&rsquo; expenditures for oncology drugs rose 55% PPPM (to $5187) from 2001 to 2011.

The proportion of patients treated with targeted drugs grew from 13% in 2001 to 43% in 2011, and the allocated insurance payments surged from 22% to 63% in the same period. A comparison of the early and later periods (2001-2005 vs 2005-2010) showed a shift toward the use of more expensive drug classes in recent years.

The shift toward targeted treatments, coupled with inflation throughout the drug lifecycle, emphasizes the need for creative use of value-based managed care tools by private payers to curb the escalating cost of cancer drugs, according to the study authors, who noted that controlling the rapid rise in spending &ldquo;will require more than current oral drug parity laws, such as value-based insurance that makes the benefits and costs transparent and involves the patient directly in the choice of treatment.&rdquo;

More aggressive management of pharmacy benefits, as well as payment reform for injectable drugs, should aid this effort.

1. &nbsp;&nbsp; Aggarwal S. Targeted cancer therapies.

2. &nbsp;&nbsp; Shih Y-CT, Smieliauskas F, Geynisman DM, Kelly RJ, Smith TJ. Trends in the cost and use of targeted cancer therapies for the privately insured nonelderly: 2001 to 2011.

2015; May 18 [Epub]. doi: 10.1200/JCO.2014.58.2320.

3. &nbsp;&nbsp; Raborn ML, Pelletier EM, Smith DB, Reyes CM. Patient out-of-pocket payments for oral oncolytics: results from a 2009 US claims data analysis.

2012;8(3 suppl):9s-15s. doi: 10.1200/JOP.2011.000516.

4. &nbsp;&nbsp; Dorn SD, Wei D, Farley JF, et al. Impact of the 2008-2009 economic recession on screening colonoscopy utilization among the insured.

2012;10(3):278-284. doi: 10.1016/j.cgh.2011.11.020.

A study published in the Journal of Clinical Oncology, May 18, 2015, details payer cost and use, as well as out-of-pocket (OOP) spending, for privately insured nonelderly patients receiving oral or intravenous (IV) chemotherapy for the treatment of cancer.

Lynda Seminara | Authors

Articles

New Research to Identify Chemo-Resistant Genes in Ovarian Cancer

PI3K Inhibition May Fuel Cancer Rather Than Fight It

Inhibiting ALK1 in Breast Cancer May Halt Metastases

Targeted Treatments Dominate Spending Landscape in Oncology