options than ever before, one
of the continuing challenges
for the clinician is how to
help the patient to manage
side effects so that the dosing
schedule can be maintained…
A very disruptive and pervasive problem with the administration of VEGF-TKI therapies is diarrhea; what causes its occurrence is poorly understood.
In a collection of studies of over 1100 patients among three of the commonly used TKI’s the overall incidence of diarrhea was 51% (chart right). To test the hypothesis that protective species of bacteria in the stool flora may be detected by bacteromic profiling, an initial study of a small group of
patients currently on VEGF-TKI
treatment was conducted. Twenty members of the study group submitted specimens of sufficient quantity to be analyzed. In those samples while 141 bacterial specie were identified there were two specie found to be more common and abundant in the eight patients in the cohort that had no significant issues with diarrhea.
Due to the small sample size in this study, with no control for dietary intake and other factors the results as expected were inconclusive. But the study indicated that bacteromic profiling may be an important first step in finding ways to reduce or eliminate the incidence of diarrhea in TKI patients. If protective bacteria are identified in subjects without diarrhea in larger studies, subsequent interventional studies may identify probiotic supplements which can be administered prophylactically to patients taking these medications.
Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 82
The Problem Is…
In renal-cell carcinoma we are considering all clear-cell carcinomas to be the same, and we are also doing this with other RCC histologies.
I would contend that they are not the same, in fact there are no two tumors that are exactly the same. As a consequence, when patients get treated we may find that the treatment works well for a set of patients – but it doesn’t work well for another set…
In the end we are left with a drug that if the number of patients that are benefitted is small we think that the drug doesn’t work. The answer may be that it does work, but only for a small group of patients.
What we need to evolve to is a model where we are treating patients with different tumor type/subtypes with different drugs. James Brugarolas, M.D., Ph.D.
University of Texas
Southwestern Medical Center Dallas, TX
B
IOLOGY-B
ASEDC
LASSIFICATION OFRCC
Dr. Brugarolas’ presentation covered the classification of genetic mutations that occur in patents with clear cell renal cell carcinoma (ccRCC). By understanding these various classifications, eventually it is hoped that a specific therapeutic drug will be used in certain patients based on their tumor’s genetic makeup.In ccRCC tumors, it is found that the VHL gene is mutated or missing 50-75% of the time. Along with the VHL gene, the PBRM1, SETD2, and BAP1 genes are also mutated in ccRCC tumors at least 10% of the time. All of these mutated genes are involved in tumor suppression, meaning that their associated proteins that signal cancer cells to stop multiplying in an uncontrollable way are disrupted allowing tumor development and growth.
There are two interesting aspects to these four genes (VHL, PBRM1, SETD2, and BAP1). First, BAP1 and PBRM1 are largely mutually exclusive. This means that when one of these genes is mutated or missing, the other is present and intact. It should also be noted that when there is a BAP1 gene
mutation, the tumor is of high grade and likewise when there is a PBRM1 gene mutation the tumor is of low grade. Second, all four of these genes are all located on chromosome 3p, the short arm of
chromosome 3. In a majority of patients with ccRCC, this portion of chromosome 3 is missing and of course meaning that copies of all four of these tumor-suppressing genes are missing.
Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 83
Studying these four genes within
chromosome 3p has led to the creation of a ccRCC development model. Kidney cancer starts with an intragenic (internal) mutation of the VHL gene. This could be an inherited condition, caused by environmental factors, or caused by toxicity factors. The loss of VHL is usually not enough for cancer to develop, as it’s thought to be a fairly low tumor effector. However, following the mutation of the VHL gene, there is many times then a loss of the 3p portion of chromosome 3. The 3p loss then leads to a mutation of PBRM1 or BAP1, which leads to the development of either a low-grade or high-trade tumor. In the future, a biopsy of a ccRCC tumor can reveal which specific genes are mutated, thus forming a biologic classification of the tumor. Based on the type of gene mutations that are found, a specific treatment drug can be chosen for the patient.
Slicing the Pie Thinner
The distribution chart at right shows the makeup of the most common subtypes of rcc.
Breaking these subtypes into smaller categories of genetic mutations could lead to better
understanding and administration of treatments for patients.
Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 84
During evaluation studies of c-MET with kidney tumors in place we found that the RCC kidney had higher expression of c-MET than the adjacent normal kidney. Clear-cell types had less expression than either papillary or sarcomatoid which were almost equal in incidence of expression. Higher grade tumors had higher levels of c-MET.
Not surprisingly, higher levels of c-MET expression correlated with lower cancer-specific survival. Various cancer treatment drugs have been developed in the past decade that target and block specific protein pathways. Examples of these for kidney cancer include VEGF pathway inhibitors (ex: sunitinib) and mTOR pathway inhibitors (ex: everolimus). The research community is in constant search for other potential protein pathway inhibitors. c-MET (also called MET) is one of these pathways that is under investigation. c-MET is a protein that helps to trigger tumor growth and contributes to angiogenesis (formation of new tumor blood vessels). Research data has shown that by inhibiting the c-MET pathway, tumor growth can be slowed.
Although protein pathway blocking drugs have shown great promise for kidney cancer patients, over time tumor resistance increases and these drugs
become less effective. Also, combinations of these drugs, specifically combining VEGF and mTOR inhibitors have proven to be very toxic.
c-Met is rarely mutated: In >400 clear cell RCCs sequenced by The Cancer Genome Atlas (TCGA) it was observed in <1% of patients. Loss of VHL results in increases in c-Met expression and normal kidney secretes
HGF hepatocyte growth factor which binds to c-Met.
Inhibition of the c-MET pathway can assist in the slowing of tumor growth.
Currently, there are several clinical trials in progress that are measuring the effectiveness of c-MET inhibitors. These trials have been mostly in a second line treatment setting, and there have been good results. Also, research data is showing that a combination of VEGFR and MET inhibition is more effective than inhibiting either pathway alone.
Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 85
Circulating tumor cells (CTCs) are tumor cells that have entered into a person’s blood circulation system. They can come from both primary and metastatic tumors. In this presentation, Dr. Joshua Lang describes research that he is working on to “filter” and extract CTCs from a patient blood sample. The hope is that in the future, reliable techniques can be developed based on this type of research to collect CTCs and use them as biomarkers to be used in a patient’s treatment plan. By examining these biomarkers, a patient’s treatment could be targeted to a specific drug. Or, the biomarkers could indicate
when a patient is beginning to develop resistance to a drug leading to switching their treatment plan.
One of the challenges when dealing with circulating tumor cells is that there are very few of them when compared to the total number of cells in the bloodstream. Dr. Lang and his team are developing very creative biomedical engineering techniques to separate CTCs from “normal” cells. This involves binding magnetic beads to the cells of interest, and then using water and oil to aid in the separation of cells. The device that they have developed is called the VERSA chip, which stands for Versatile, Exclusion-Based, Rare, Sample, Analysis chip. This device provides for
comprehensive molecular analysis of a blood sample, providing for DNA and RNA extraction.
Our great hope is that this process will allow us to truly personalize the therapies that we are giving to our patients so that we can say “based on certain therapies this is a therapy that is going to be
effective”. If the test indicates otherwise it will allow us to move to the next treatment option we have available.
…it is an opportunity to continue to challenge and reinform the work we do…