Talk Wslides

.
Mathematics Meets Oncology

. Mathematical Oncology
Philippe B. Laval
Kennesaw State University
November 12, 2011
Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology
November 12, 2011
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Outline
. Introduction: motivation for the talk. . 2 Why mathematicians and cancer researchers should collaborate more. . 3 Overview of cancer.
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. Some tumor growth models. . 5 Conclusion.

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Introduction: Motivation for the Talk
This talk is motivated by two facts:

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. There is a need for mathematicians and cancer researchers to work together. This is echoed in many papers and books I have read. A recent search on the PubMed database showed that out of about 1.5 million papers listed on cancer research, only 5% were related to mathematical modeling.
November 12, 2011
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This talk is motivated by two facts: . There is a need for mathematicians and cancer researchers to work together. This is echoed in many papers and books I have read. A recent search on the PubMed database showed that out of about 1.5 million papers listed on cancer research, only 5% were related to mathematical modeling. . 2 "I love math and science, I want to make a dierence but I dont want
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to teach. What can I do?"
November 12, 2011
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This talk is motivated by two facts: . There is a need for mathematicians and cancer researchers to work together. This is echoed in many papers and books I have read. A recent search on the PubMed database showed that out of about 1.5 million papers listed on cancer research, only 5% were related to mathematical modeling. . 2 "I love math and science, I want to make a dierence but I dont want
1
to teach. What can I do?" . It looks like we should arrange this marriage between 3 mathematicians and cancer researchers!
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Why Mathematicians and Oncologists Are Not Working Together
Cancer is still not fully understood. It is hard to model a situation we do not understand.
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Cancer is still not fully understood. It is hard to model a situation we do not understand. The parts of cancer we do understand are extremely complex, thus dicult to model.
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Cancer is still not fully understood. It is hard to model a situation we do not understand. The parts of cancer we do understand are extremely complex, thus dicult to model. Mathematical models are too simplistic and cannot model realistically a disease as complex as cancer.
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Cancer is still not fully understood. It is hard to model a situation we do not understand. The parts of cancer we do understand are extremely complex, thus dicult to model. Mathematical models are too simplistic and cannot model realistically a disease as complex as cancer. The mathematics involved in these models is dicult and scares away non mathematicians.
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What Would Be Gained if They Worked Together
Mathematicians are not going to nd a cure for cancer. However, they can help in the following areas: There is an enormous amount of data generated by the various experiments and clinical trials being conducted around the world. This data needs to be analyzed. This is the work of statisticians.
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Mathematicians are not going to nd a cure for cancer. However, they can help in the following areas: There is an enormous amount of data generated by the various experiments and clinical trials being conducted around the world. This data needs to be analyzed. This is the work of statisticians. Once we understand a mechanism involved with cancer, we can model it. We can then run simulations using the models. These simulations allow us to:
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Validate theories.
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Validate theories. Predict the outcome of a disease.
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Validate theories. Predict the outcome of a disease. Finding the optimal dosage for a certain medicine.
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How We Can Fix It
Involve more mathematicians in cancer research. It begins early on, at the undergraduate level. After briey introducing what cancer is, we will present models which can be discussed in undergraduate classes.
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What is Cancer?
The Cancer Process
. The development and healthy life of a human being requires the cooperation of more than 50 trillion cells.
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What is Cancer?
The Cancer Process
. The development and healthy life of a human being requires the cooperation of more than 50 trillion cells. . 2 This cooperation is maintained by numerous checks and balances
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which determine when and how a cell will divide, dierentiate or die. For every process which can take place, there are factors to promote it and factors to inhibit it.
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What is Cancer?
The Cancer Process
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which determine when and how a cell will divide, dierentiate or die. For every process which can take place, there are factors to promote it and factors to inhibit it.
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. The phenomenon of cancer can be dened on various levels. On the most basic level, cancer represents a collapse of this cooperation.
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What is Cancer?
The Cancer Process
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which determine when and how a cell will divide, dierentiate or die. For every process which can take place, there are factors to promote it and factors to inhibit it. . The phenomenon of cancer can be dened on various levels. On the most basic level, cancer represents a collapse of this cooperation. . 4 Though cancer is a whole collection of diseases, all cancer cells have
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common features:
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What is Cancer?
The Cancer Process
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common features:
They grow without control.
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What is Cancer?
The Cancer Process
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common features:
They grow without control. They cease to perform their functions. Their main and only goal is to grow.
. . . . . .
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What is Cancer?
How a Cell Becomes Cancerous
All cancers start from a single cell that undergoes many changes. Some of those changes are permanent alterations to the DNA called mutations. Luckily, our bodies have a host of defensive strategies for making sure damaged or mutated cells never get the chance to reproduce. Even if they cant always stop the process of cancer development, our natural defenses slow it down. This process takes years, even decades. Over our lifetimes, thousands and thousands of damaged cells get disposed of before they can cause any harm. But if a cell does manage to get past our defenses and start multiplying without control, it can form a mass of abnormal cells called a tumor. Not all tumors are dangerous. Those that arise and then go quiet are called benign. But malignant or cancerous tumors can spread into surrounding tissues, damaging nearby cells or organs.
. . . . . .
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Stages of Tumor Growth

There are three distinct stages (avascular, vascular, metastatic) to cancer development.
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. Avascular: Tumor cells grow at a much faster rate than the host cells, requiring more and more nutrients and creating more and more waste to dispose of. After a while, the hosts cells cannot satisfy the demands of the tumor and the tumor starves. It cannot grow anymore. Unless something else happens, tumors will remain small (less than a few mm in diameter) and will not spread.
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There are three distinct stages (avascular, vascular, metastatic) to cancer development. . Avascular: Tumor cells grow at a much faster rate than the host cells, requiring more and more nutrients and creating more and more waste to dispose of. After a while, the hosts cells cannot satisfy the demands of the tumor and the tumor starves. It cannot grow anymore. Unless something else happens, tumors will remain small (less than a few mm in diameter) and will not spread. . 2 Vascular: Many tumor cells have the ability to develop their own
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blood supply (angiogenesis). Since they are not starved, tumors which reach this stage can continue growing and invade surrounding tissues.
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There are three distinct stages (avascular, vascular, metastatic) to cancer development. . Avascular: Tumor cells grow at a much faster rate than the host cells, requiring more and more nutrients and creating more and more waste to dispose of. After a while, the hosts cells cannot satisfy the demands of the tumor and the tumor starves. It cannot grow anymore. Unless something else happens, tumors will remain small (less than a few mm in diameter) and will not spread. . 2 Vascular: Many tumor cells have the ability to develop their own
1
blood supply (angiogenesis). Since they are not starved, tumors which reach this stage can continue growing and invade surrounding tissues.
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. Metastatic: Once a tumor has acquired its own blood supply, some of its cell can escape the primary tumor via the circulatory system (metastasis) and set up secondary tumors elsewhere in the body.
. . . . . .
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Angiogenesis?
Illustration of Angiogenesis
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Tumor Growth Models
We will only present models, not discuss them in detail or solve them. The goal is to give a sample of the methods used and show that simple cancer models can be presented early on in undergraduate classes. We will present models using ODEs as well as PDEs. The ODE models view cancer as a population of cells and study how the population evolves. Thus, traditional population models can be used. The PDE models are more spatially structured. They allow to make a dynamic description of spatial variations in the system.
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Avascular Tumor Growth - ODE Models

Homogeneous Solid Tumors - Logistic Growth
As noted above, avascular tumors cannot grow beyond a certain size. This is because as the tumor increases in size, competition for nutrients and space cannot be neglected anymore. Therefore, we cannot use the exponential growth law. Instead, we use the logistic growth law. ( ) N dN = kN 1 dt N N (0) = N0 > 0 The solution is N (t ) = N N0 N as t N0 + (N N0 ) e kt
where: N (t ) is the number of cells within a tumor. k > 0 is the net rate at which the cells proliferate. N > 0 is the carrying capacity of the population. . .
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Homogeneous Solid Tumors - Modied Logistic Growth
The symmetry of the previous solution about its inection point makes it dicult to t experimental data. So a modied version is used instead. ( ( ) ) k N dN = N 1 dt N N (0) = N0 > 0 The solution is ( N ( t ) = N
N0 + (N N ) e kt N0 0
)1
Note that when = 1, we have the logistic model. The Gompertzian law is recovered in the limit as 0+ .
. . . . . .
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Gompertzian Law
Named after Benjamin Gompertz (1779-1865) and adapted in the 1960s to tumor growth. N dN = kN ln dt N N (0) = N > 0 0 The solution is N (t ) = N e ln N e
N0
kt
N as t
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Comparing the Solutions
)1 N0 for We plotted g (N0 , , N , k, t ) = N N0 + (N N0 ) e kt N0 = 0.1, N = 1, k = 0.1 and various values of shown in the table: 0.5 1 1.5 2 Color red black green blue (
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Treatment of Homogeneous Solid Tumors
Consider a tumor which would follow logistic growth without therapy. The patient undergoes chemotherapy. The patient is injected a drug which kills cancer cells upon contact. Let A (t ) be the drug concentration within the tumor, is the rate at which the drug kills the tumor, is the decay rate of the drug, is the rate at which the drug becomes ineective after it has killed tumor cells and a (t ) is the rate at which the drug is being delivered. Then, the following model can be used: ) ( dN = kN 1 N AN dt N dA = a (t ) A AN dt N (0) = N0 and A (0) = A0
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To keep the system fairly simple, we can consider two methods of infusion.
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. Continuous infusion: a (t ) = a t 0
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To keep the system fairly simple, we can consider two methods of infusion.
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. Continuous infusion: a (t ) = a t 0
. Periodic infusion: { a (t ) = a if n < t < n + 0 if n + < t < n + 1
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Tumor Growth - PDE Models

Gatenby, 1996
This next model explains how tumor cells can grow by killing surrounding healthy tissue. They do so by modifying the microenvironmental pH. Cancer cells resist better to an environment with excess acid than healthy cells. N1 (x, t ): density of normal tissue with growth rate r1 and carrying capacity K1 . N2 (x, t ): density of neoplastic tissue with growth rate r2 and carrying capacity K2 . L (x, t ): excess concentration of H + ions.
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Gatenby, 1996
The behavior of the normal tissue is determined by: . 1 Logistic growth of N . 1 . 2 Population competition with neoplastic tissue with Lotka-Volterra competition strength parameter 12 . . 3 Interaction of N with excess H + ions leading to a death rate 1
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proportional to L. . Cellular diusion with an N2 -dependant coecient DN [N2 ] 1
The behavior of the neoplastic tissue is similar, except for dying from excess H + ions.
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Gatenby, 1996
We assume that the excess H + ions satisfy: . 1 They are produced at a rate proportional to N with rate r . 2 3 . 2 They diuse chemically with diusion coecient D . 3
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. An uptake term is included to account for the body trying to eliminate the excess acid with reabsorption rate d3 .
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Gatenby, 1996 - The Model
Putting the above together, we obtain ( ) N1 = r N 1 N1 N2 d LN + (D [N ] N ) 1 1 12 1 1 2 1 N1 t K2 ) (K1 N1 N2 N2 21 + (DN2 [N1 ] N2 ) = r2 N2 1 t K2 K1 L = r3 N2 d3 L + D3 L t
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Tumor Growth - Angiogenesis
How can we take into account angiogenesis?

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. Incorporate angiogenesis into existing models: All the above models used a constant carrying capacity. With angiogenesis, the carrying capacity will increase. We make it a function of time. Which function to use is determined by available data.
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Tumor Growth - Angiogenesis
How can we take into account angiogenesis? . Incorporate angiogenesis into existing models: All the above models used a constant carrying capacity. With angiogenesis, the carrying capacity will increase. We make it a function of time. Which function to use is determined by available data. . 2 Create new models: Incorporate the process of angiogenesis in the
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model. This requires adding variables for all the chemical components involved and the equations which describe this process. The resulting models are much more complicated. They are still work in progress as angiogenesis is extremely complex and not fully understood.
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Conclusion
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. Cancer is one of the main causes of mortality in the world, thus cancer research is one of our main priorities.
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Conclusion
. Cancer is one of the main causes of mortality in the world, thus cancer research is one of our main priorities. . 2 Mathematicians are not going to nd a cure for cancer. However, they
1
are needed in cancer research to help analyze the enormous amount of data generated by the various experiments and clinical trials being conducted around the world. They are also needed to help develop and validate new mathematical models. These models can in turn be used to run simulations, test theories, help determine the optimum dosage of new medicines being developed.
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Conclusion
. Cancer is one of the main causes of mortality in the world, thus cancer research is one of our main priorities. . 2 Mathematicians are not going to nd a cure for cancer. However, they
1
are needed in cancer research to help analyze the enormous amount of data generated by the various experiments and clinical trials being conducted around the world. They are also needed to help develop and validate new mathematical models. These models can in turn be used to run simulations, test theories, help determine the optimum dosage of new medicines being developed.
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. If you love mathematics and science and you want to make a dierence but you do not want to teach, a career in cancer research may be for you. You are needed. We can adapt John F. Kennedys quote to say: Dont ask what cancer research can do for you, but what you can do for cancer research!
. . . . . .
November 12, 2011
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Mathematics Meets Oncology

November 12, 2011

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

. Some tumor growth models. . 5 Conclusion.

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Introduction: Motivation for the Talk

This talk is motivated by two facts:

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Introduction: Motivation for the Talk

to teach. What can I do?"

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Introduction: Motivation for the Talk

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Why Mathematicians and Oncologists Are Not Working Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Why Mathematicians and Oncologists Are Not Working Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Why Mathematicians and Oncologists Are Not Working Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Why Mathematicians and Oncologists Are Not Working Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

What Would Be Gained if They Worked Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

What Would Be Gained if They Worked Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

What Would Be Gained if They Worked Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

What Would Be Gained if They Worked Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

What Would Be Gained if They Worked Together

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

How We Can Fix It

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011

Philippe B. Laval (Kennesaw State University) Mathematics Meets Oncology

November 12, 2011