Genetic approach to cancer may be more complex than previously known

[heblaj01]

In this article the researchers present their findings which show a greater number of genes involved in cancer, a complicating factor in genetic treatment research.
The plus side of the story is a better definition of research targets helped by faster gene identification methods.

http://www.sanger.ac.uk/Info/Press/2007/070307.shtml
Drivers and Passengers on the Road to Cancer

Largest genome study of cancer types finds many mutations

[gdpawel]

According to some researchers, cancer is about the properties of evolutionary populations of cells. They feel that three conditions must be satisfied for effective control of cancer or finding its cure: comprehensiveness, specificity and knowability.

Comprehensivenss refers to the ability to kill or inactivate all malignant cells in the patient (if one malignant cell escapes, it could multiply and cause progressive disease). Specificity refers to the ability to target cancer cells without harming normal cells or causing toxicity to the patient. Knowability refers to the need to target properties of cancer that can be known, or accurately predicted.

Targeting genetic alterations can provide a basis for specificity but not comprehensiveness and knowability. The diverse, evolutionary nature of cancer implies that the required target for the consistent and specific cure or control of cancer is all the sets of malignant cells that could evolve. An approach targeting a lesser set will fail. It cannot satisfy the requirements for targeting an evolutionary population of malignant cells.

The set of all malignant cells that could evolve must apply to all pathways of tumor cell evolution and all combinations of genetic and epigenetic alterations. It must be independent of any particular pathway of tumor cell evolution. The normal cellular machinery that potentially can carry out malignant behavior is encoded within the normal human genome, essentially the same for all types of cancer, and reflected in normal processes such as wound healing.

Finding mutations in kinase genes is neither surprising nor really good news. If you're trying to figure out how many combinations of these mutations one could have, and then consider that mutations are only the beginning because it depends on the factors which regulate those genes, and how much the genes are expressed or repressed, and how all those things interact with all the other things which are going on, it is going to be a major challenge if you want to build a model of cancer cells from the bottom up.

Without cell culture, gene therapy would be beyond imagination. Tissue culture methods have made gene therapy possible. The ability to transfect cultured cells with DNA gene sequences has allowed scientists to assign functions to different genes and understand the mechanisms that activate or redress their function. The interaction between cell biology and genetics gave birth to molecular biology.

Cell culture assays with cell-death endpoints allows the identification of clinically relevant gene expression patterns which correlate with clinical drug resistance and sensitivity for different drugs in specific diseases. There is no single gene whose expression accurately predicts therapy outcome, emphasizing that cancer is a complex disease and needs to be attacked on many fronts.

Cell culture assays using the whole cell profiling method assess the activity of a drug upon combined effect of all cellular processes, using combined metabolic and morphologic endpoints. Other tests that identify DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process. Drug resistance and sensitivity is multifactorial, and the one advantage of whole cell profiling is that it can show this at the cell population level, measuring the interaction of the entire genome.

Sources:

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

[heblaj01]

Thanks gdpawel for your post. It reinforces my long held doubts that the genetic approach is the best in cancer treatment research. On the one hand trying to tackle all oncogenes at the same time is looking as an impossible task (since a master "switch" has yet to be found) which also implies a high probability of adversely affecting the life sustaining processes of normal cells. On the other hand targetting a few genes may lead to a treatment only effective until cancer cells use the neglected genes to grow again. In addition treatments based on a handfull of genes means targetted treatments which also means a lot of research to find the many specialized drugs.

This is why I tended to place more confidence in research of treatments which rely on processes less subject to multiple mutations such as virus based or the control of angiogenesis. Even this latter approach involves the possibility of affecting normal functions as wound healing & pregnancy. The extraordinary results obtained in 1998 on mice treated with the antiangiogenesis combo of Angiostatin+Endostatin have not been tried in humans & may never translate. But even if antiangiogenesis does not provide, in the end, a cure it has a better than average chance to eventually stabilize cancer at a low level devoid of symptoms akin to properly treated type 2 diabetes.

[gdpawel]

Good point heblaj01, about the possibility of affecting normal functions as wound healing. Gastrointestinal perforation has occurred in an increased incidence in patients using the angiogenesis drug Avastin. If Avastin is given within at least 28 days following major surgery (or before), it results in an abscess formation. This is due to the impaired wound healing induced by Avastin.

If Avastin works like it is supposed to work, not only does it cut off blood supply to the tumor, it also cuts off blood supply to the colon entirely causing the tissue to die. Avastin can cause you to loose your colon. What is disturbing is oncologists' comment that this is common with Avastin, BUT is never mentioned until it is too late.

Most bowel perforations with Avastin have been in cases where there is tumor going right through the wall of the colon. Avastin causes the tumor to melt away, leaving a hole. With Avastin, the tumor dissolves, but scar tissue won't form, because it can't make a blood supply.

The same thing applies to bowl perforations with Avastin in advanced ovarian cancer. Ovarian cancer commonly involves bowel walls. The problem is a direct result of the drug's ability to kill tumor cells that have replaced healthy bowel tissue, leading to a dead area that then perforates. With conventional chemotherapy, as the tumor melts away, new connective tissue forms a patch. But Avastin can inhibit the growth of capillaries into newly forming normal tissue, as well as in tumor tissue.

There are good sides and bad sides to all drugs. What needs to be learned, and obviously sometimes the hard way, is how do drugs work. This is particularly true when they are biologics, they can be working in ways and speed that we weren't used to. It is a learning process and it can be a painful one.

Avastin is still a very good drug, but we just need to learn how to use it. Molecular assays can't tell you how a drug works, it can only tell you if it works, or not.

[Lani]

true immunotherapy would be a great approach as well...

[Hopeful]

I was doing some research last week into the prognostic effect of having a tumor with combined IDC/DCIS, which led me into some fascinating work on cell mediated immunity by Dr. Maurice M. Black, noted bc oncologist, in the 1970's and '80's. (Dr. Black died in 1996). Here is a link to an abstract of one of his final papers, entitled "Prognostic Significance of in situ carcinoma associated with invasive breast carcinoma. A natural experiment in cancer immonology?": http://www.ncbi.nlm.nih.gov/entrez/q...ubmed_Abstract


His work in the 70's and 80's in the field of cell mediated immunity led him to conclude that DCIS, in some patients, contributed to the patient's immune system developing a defense against bc, and that patients with prior or concurrent DCIS to their IDC had a much lower rate of recurrence. His experiments involved the application of cells from the excised tumo on a "scratch test" on the same patient, keeping the tumor cells in contact with the scratch on the skin for 30 hours, then analyzing the skin response. In about 25% to 30% of cases, the patients' body had developed an immune response against their bc. He tested the same patients over a long period of time, to see if he got several positive tests, just one, or a combination of positive and negative. Just one positive test result seemed to greatly increase the chances for increased disease free survival of the patient. He then began to wonder if something could be done to augment the natural immune response of patients with negative results. He stated:

"Preliminary studies in our laboratory have shown that negative-to-positive changes in specific reactivity may be induced in up to 50% of postoperative, metastasis-free, bc patients treated with high doses of vitamin A and/or vitamin E. If agents that increase specific cell meidated immunity (CMI) are theraupeutically beneficial, it should follow that agents that reduce such reactivity have the potential of exerting a prognostically unfavorable effect. This possiblity should be considered in the evaluation of the effects of cytotoxic adjuvant chemotherapy, because such treatment has the potential to impair CMI responses. Since cytotoxic chemotherapeutic agents are preferentially active against cancers with poorly differentiated nuclei, we submit there is a need for the study of the influence of adjuvant chemotherapy in relation to nuclear grade and specific CMI.
Particular attention should be paid to the possibility that adjuvant chemotherapy might have deleterious effects on CMI-positive patients having breast cancers with well-defined nuclei. Such patients are less likely to experience the tumor-retarding effects of the treatment while being more likely to experience a diminution of their prognostically favorable immunity."

Hopeful

[gdpawel]

Tumor immunotherapy studies were prematurely abandoned during the early 90's. One such study was a concept of in situ cancer vaccination based upon studies of biologic response modifiers in an assay. Preliminary results found a striking association between the activity of biologic response modifiers which activate macrophages and the prior treatment status of patients with breast and ovarian cancers. Effective chemotherapy produced a massive release and processing of tumor antigens, which led to a state in which the human immune system, via in situ cancer vaccination, responded to exogenous macrophage activation signals with potent and specific anti-tumor effects.

I'm also glad to see the resurgence of aggressive cancer vaccine research. Criticism of this research would be typical of those that favor attempts to identify one-size-fits-all treatments through trial-and-error testing. Circumscription of the clinical initiative by researchers to help patients advances a naive fundamentalism. The choice of researchers to integrate promising insights and methods remains an essential component of new paradigms of cancer treatment.

[Lani]

repeating it here--showing how complex immunotherapy is as well...it seems ONE of her2+ tumors' ways of evading her2+ vaccines:
Mechanisms Involved with Tumor Relapse Identified: Researchers work toward creating a tailored breast cancer vaccine [Virginia Commonwealth University]
Researchers at Virginia Commonwealth University's Massey Cancer Center studying the interaction between the immune system and cancer cells have identified interferon gamma as one of the signaling proteins involved with tumor relapse.

The findings may help researchers develop tailored vaccines and other immunotherapeutic strategies to fight a number of cancers. Immunotherapy involves the manipulation of the immune system - by introducing an antibody or lymphocytes, or immunization with a tumor vaccine - to recognize and eradicate tumor cells.

Using a transgenic mouse model of breast cancer, researchers found that interferon gamma, a cytokine or chemical messenger that is produced by cells of the immune system upon activation, plays a role in tumor relapse. In humans, interferon gamma is also produced by white blood cells of the immune system in response to invasion by pathogens or tumors in order to protect the host against infection or cancers. Production of interferon gamma by lymphocytes against tumors is considered a sign of good prognosis; however, recent study findings indicate that this may not be the case. The findings were reported in the March 2007 issue of the European Journal of Immunology, the official journal of the European Federation of Immunological Societies.

"By understanding the molecular mechanisms involved with tumor relapse, we can create tailored vaccines that can induce specific types of immune responses in patients, rather than inducing a broad range of immune responses - some of which may be detrimental or may induce tumor relapse," said lead investigator, Masoud H. Manjili, D.V.M., Ph.D., a member scientist with the Massey Cancer Center.

"Ultimately, we hope to offer a new polypeptide vaccine approach that induces tumor killing without causing HER-2/neu loss. Loss of HER-2/neu is a mechanism that tumors utilize to escape the immune-mediated destruction," he said.

Since 2000, Manjili and his colleagues have been employing animal models of breast cancer to evaluate anti-tumor efficacy of a vaccine formulation they created. This vaccine formulation combines a heat shock protein 110 (HSP110), as an adjuvant, with a tumor antigen HER-2/neu, as a protein target expressed in breast tumors. Adjuvants are agents that are able to modify another agent - basically working as a chemical catalyst.

The work is supported by the National Cancer Institute and the Susan G. Komen Breast Cancer Foundation.


ABSTRACT: HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses [European Journal of Immunology]
Induction of tumor-specific immune responses results in the inhibition of tumor development. However, tumors recur because of the tumor immunoediting process that facilitates development of escape mechanisms in tumors. It is not known whether tumor escape is an active process whereby anti-tumor immune responses induce loss or downregulation of the target antigen in the antigen-positive clones. To address this question, we used rat neu-overexpressing mouse mammary carcinoma (MMC) and its relapsed neu antigen-negative variant (ANV). ANV emerged from MMC under pressure from neu-specific T cell responses in vivo. We then cloned residual neu antigen-negative cells from MMC and residual neu antigen-positive cells from ANV. We found marked differences between these neu-negative clones and ANV, demonstrating that the residual neu-negative clones are probably not the origin of ANV. Since initial rejection of MMC was associated with the presence of IFN-?-secreting T cells, we treated MMC with IFN-? and showed that IFN-? could induce downregulation of neu expression in MMC. This appears to be due to methylation of the neu promoter. Together, these data suggest that neu antigen loss is an active process that occurs in primary tumors due to the neu-targeted anti-tumor immune responses.