Trailblazer in the Development of Combination Chemotherapy

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Advances in cancer therapy increasingly reflect the application of genomics and proteomics to target tumor-specific phenomena. Several insights have accelerated this process including the primacy cell survival signals in carcinogenesis and drug resistance and the growing appreciation of tumor biology as contextual.

Cell function analysis of programmed cell death addresses both issues by measuring metabolic and morphologic features of drug induced cell death (apoptotic and non-apoptotic) using native cultures isolated from surgical specimens and cytologically + fluids. The predictive validity of this functional profiling platform established for cytotoxics, has led to this platforms current focus on signal transduction. A cell "function" exploration of "vertical" and "horizontal" signal inhibition.

By expanding beyond current FDA-approved drugs into the new agents that target PI3K, AKT, TORC1&2, MEK/ERK and c-MET, functional profiling can facilitate developmental therapeutics. Analyses are now examining the activity and synergy of EGFR-TKIs with VEGF, mTOR, MEK/ERK, PI3K, AKT and c-MET inhibitors in various diseases.

There are lots of things that determine if drugs work, beyond the existence of a given target. Does the drug even get into the cancer cell? Does it get pumped out of the cell? Does the cell have ways of escaping drug effects? Can cells repair damage caused by the drug? Do combinations of drugs work in ways which can't be predicted on the basis of static gene expression patterns?

There are a number of drugs that could hold benefit for the patient with ovarian cancer and a number of novel combinations. Drugs are tested for activity both as single agents and in rational drug combinations, in order to assess possible drug synergies.

This involves using functional profiling analysis that allows for simultaneous identification of anti-tumor activity and anti-vascular activity in established anti-cancer drug treatments and also in novel combinations of standard drugs, kinase-inhibiting drugs and anti-angiogenesis agents.

Literature Citation:

Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007
Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)

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Robert A. Nagourney, M.D.

The New York Yankees catcher Yogi Berra famous quote, “DéjÃ* vu all over again,â€� reminds me of the growing focus on the concept of “N- of-1.â€� For those of you unfamiliar with the catchphrase, it refers to a clinical trial of one subject.

In clinical research, studies are deemed reportable when they achieve statistical significance. The so-called power analysis is the purview of the biostatistician who examines the desired outcome and explores the number of patients (subjects) required to achieve significance. The term “N� is this number. The most famous clinical trials are those large, cooperative group studies that, when successful, are considered practice-changing. That is, a new paradigm for a disease is described. To achieve this level of significance it is generally necessary to accrue hundreds, even thousands of patients. This is the “N� that satisfies the power analysis and fulfills the investigators expectations.

So what about an N-of-1? This disrupts every tenet of cancer research, upends every power analysis, and completely rewrites the book of developmental therapeutics. Every patient is his or her own control. Their good outcome reflects the success or failure of “the trial.� There is no power analysis. It is an “N� of 1.

This “breakthrough� concept however, has been the underpinning of the work of investigators like Drs. Larry Weisenthal, Andrew Bosanquet, Ian Cree, myself and all the other dedicated researchers who pioneered the concept of advancing cancer outcomes one patient at a time. These intrepid scientists described the use of each patient’s tissue to guide therapy selection. They wrote papers, conducted trials and reported their successful results in the peer-reviewed literature. These results I might add have provided statistically significant improvements in clinical responses, times to progression, even survival. By incorporating the contribution of the cellular milieu into clinical response prediction, these functional platforms have consistently outperformed their genomic counterparts in therapy selection So why, one might ask, have the efforts of these dedicated investigators fallen on deaf ears?

I think that the explanation lies in the fact that we live in a technocracy. In this environment, science has replaced religion and medical doctors have abdicated control of clinical development to the basic scientists and basic scientists love genomics. It is no longer enough to have good results; you have to get the results the right way. And so, meaningful advances in therapeutics based on functional platforms have been passed over in favor of marginal advances based on genomic platforms.

There is nothing new about N-of-1. It has been the subject of these investigators compelling observations for more than two decades. Though functional platforms are not perfect, they provide a 2.04 (1.62 to 2.57, P < 0.001) fold improvement in clinical response for virtually all forms of cancer – as we will be reporting (Apfel C, et al Proc ASCO, 2013).

It seems that in the field of cancer therapeutics “perfect is the enemy of good.� By this reasoning, good tests should not be used until perfect tests are available. Unfortunately, for the thousands of Americans who confront cancer each day there are no perfect tests. Perhaps we should be more willing to use good ones while we await the arrival of perfect ones. After all, it was Yogi Berra who said, “If the world was perfect, it wouldn’t be.�

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Combination chemotherapy is harsh. The drugs are poisons. Side effects can be severe. Nausea and vomiting, while better controlled today, remain a problem. Weakness, fatigue, low white blood cell counts, infections, hair loss, and nerve damage, the list is long.

There are also significant long-term problems, including heart disease, brain dysfunction, hearing loss and the development of new cancers. Most anticancer drugs are carcinogenic. Nonetheless, the fact remains that almost every person that has ever been cured of metastatic cancer has been cured by "combination" chemotherapy (a small number of patients have been cured by immunotherapy). The approach has proven successful in a wide range of cancers (Frei E. et al, Cancer Res. 1985 Dec;45:6523-37).

The problem is that combination chemotherapy has run into a brick wall. It has not proven possible to extend the success of combination chemotherapy in childhood cancers, leukemia, lymphoma, and testicular cancer to cancer in general. The common metastatic cancers such as breast, lung, colon, prostate, bladder, kidney, melanoma, ovarian, and pancreatic have resisted cure by combination chemotherapy.

It is not that there has been no progress, but it has been painfully slow and limited. All too often patients and their physicians are confronted with the depressing task of balancing the severe side effects of chemotherapy and their negative impact on the quality of life against potential survival benefits.

The second reason that cure has been largely abandoned as a research goal is the complexity of the disease. What previously had been hidden is now exposed to plain view. We can now look inside the black box of the cancer cells. What we see is chaos. Every cell is different, and the cancer cells keep changing, even in the same patient.

The problem is tumor cell evolution. To achieve cure, therapy must address the problem of tumor cell evolution. Cancer can be cured. This is a fact. Thousands of patients are alive today, cured of metastatic cancer.

In 1985 Dr. Frei wrote: "To the extent that physicians and investigators are ambivalent with respect to the term 'cure,' patients and the medical community will be skeptical. One of the obstacles to progress in cancer therapy generally and in cancer chemotherapy specifically has been the presence of such skepticism" (Frei E. et al, Cancer Res. 1985 Dec;45:6523-37).

Reference: "Cure: Scientific, Social and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al. 2005

http://cancerfocus.org/forum/showthread.php?t=3371

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Accuracy and clinical utility of in vitro cytometric profiling to personalize chemotherapy: Preliminary findings of a systematic review and meta-analysis.

Sub-category: Molecular Diagnostics and Imaging

Category: Tumor Biology

Meeting: 2013 ASCO Annual Meeting

Abstract No: e22188

Citation: J Clin Oncol 31, 2013 (suppl; abstr e22188)

Author(s): Christian Apfel, Kimberly Souza, Cyrill Hornuss, Larry Weisenthal, Robert Alan Nagourney; SageMedic, Inc, Larkspur, CA; Ludwig Maximilians University of Munich, Munich, Germany; Weisenthal Cancer Group, Huntington Beach, CA; Rational Therapeutics, Long Beach, CA

Abstract:

Background:

Cytometric analysis, or in-vitro functional profiling, has been developed as a method to predict tumor response to different drugs with the premise to personalize chemotherapy and improve patient outcomes.

Methods:

We performed a systematic review and a meta-analysis a) of correlative studies using cytometric profiling that reported diagnostic accuracy (sensitivity and specificity) and b) of effectiveness studies comparing patient outcomes when allocated to treatment guided by a cytometric assay versus population-based standard of care. We used Meta-DiSc software to find pooled sensitivity and specificity and analyze the summary receiver operating characteristic (sROC) curve and used Review Manager 5.1 to generate forest plots on overall tumor response (50% or greater decrease in tumor diameter) and on 1-year overall survival.

Results:

We included 28 mostly retrospective trials (n=664) reporting accuracy data and 15 prospective trials (n=1917) reporting therapeutic efficacy data. The accuracy of correlative study revealed an overall sensitivity of 0.922 (95% confidence interval 0.888 to 0.948), specificity of 0.724 (95% CI 0.669 to 0.774) and an area under the sROC curve of 0.893 (SE=0.023, p<0.001). Studies comparing the clinical utility revealed a two-fold overall tumor response for an assay-guided therapy versus standard of care therapy (odds ratio 2.04, 95% CI 1.62 to 2.57, p<0.001). Similarly, patients who received assay-guided therapy compared to those who received standard of care or physician’s choice had a significantly higher 1-year survival rate (OR 1.44, 95% CI 1.06 to 1.95, p=0.02).

Conclusions:

Despite various limitations of individual studies, the aggregate and fairly consistent evidence of these data suggests cytometric profiling to be accurate, to improve overall tumor response, and to increase 1-year patient survival. Given the enormous potential for our society, a well-designed and sufficiently-powered randomized controlled trial is urgently needed to validate these results.

http://abstracts2.asco.org/AbstView_132_118466.html

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International collaboration in personalized medicine for the treatment of advanced and drug-refractory cancers: Clinical application of human tumor primary culture analyses.

Sub-category: Cytotoxic and Other Novel Agents

Category: Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics

Meeting: 2013 ASCO Annual Meeting

Abstract No: e13562

Citation: J Clin Oncol 31, 2013 (suppl; abstr e13562)

Author(s): Fabricio Colacino Silva, Fernando C. Maluf, Antonio C. Buzaid, Robert Alan Nagourney, Nise Hitomi Yamaguchi, Paulo D'Amora, Steven Evans, Paula J Bernard, Federico Francisco; Hospital do Cancer Alfredo Abrao, Campo Grande, Brazil; Hospital Sirio-Libanes, São Paulo, Brazil; Hospital São José, São Paulo, Brazil; Rational Therapeutics, Long Beach, CA; Institute of Advances in Medicine and Hospital Albert Einstein, Sao Paulo, Brazil; Centro de Genomas, Sao Paulo, Brazil

Abstract:

Background:

Personalized oncology has advanced through genomic and proteomic platforms. BCR-abl; EGFr and ALK have provided drug-able targets and companion diagnostics in several diseases, yet many transforming events in humans are polygenic, complex and incompletely understood at a genomic level. Recognition that oncogenesis reflects changes in the cell and its micro environment has renewed interest in whole cell experimental models that capture native-state cell-cell, -stroma and -vascular signaling. Ex vivo analysis of programmed cell death (EVA/PCD) has been shown to correlate significantly with response, time to progression and survival (Nagourney, R. Curr. Treat Op Oncol, 2006).To explore EVA/PCD functional profiling in Brazil, hospital-based investigators, Centro de Genomas and Rational Therapeutics coordinated the transport of 67 surgical specimens for analyses.

Methods:

Dose-response curves using metabolic (ATP-content, mitochondrial) and morphologic endpoints, interpolated to LC50's and synergy by median-effect, were compared with databases to identify patient-specific profiles for cytotoxics, targeted agents and combinations. Reports provided day 7.

Results:

62/67 (92%) provided adequate tumor for analysis; 39 male (58%); 28 (42%) female; 6 chemo-naive and 61 previously treated. Results provided for < 8 drugs in 14/62 (22%); 8-16 drugs in 34/62 (54%) and > 16 drugs in 14/62 (22%). Of 22 tumor types, breast (8); Melanoma (8); NSCLC (8); ovary (7); pancreas (7) and sarcoma (4) predominated. EVA/PCD was used to select the most active combinations. Agents selected, response rates and durations are being tabulated and will be reported.

Conclusions:

The transport, processing and reporting of human tumor primary culture analyses is feasible, providing results in 92% of specimens and median of 12 drugs evaluated (range 4-32). Preliminary outcomes in these drug-refractory patients reveal that novel, often unexpected drug combinations (Everolimus and Lapatinib in triple negative breast) were identified and provided objective tumor responses, supporting EVA/PCD in therapy selection (personalized therapy) and drug development.

http://abstracts2.asco.org/AbstView_132_117655.html