Invented by Yibin Kang, Guohong Hu, Princeton University
The Princeton University invention works as followsThe present invention is a method for identifying cancer patients who have a poor prognosis. It also relates to therapeutic methods that improve prognosis through combating metastasis in cancer cells and removing chemoresistance. The embodiments of the invention allow for objective prognostication of a cancer incident, and in particular breast cancer. Immunotherapy and antisense therapy are two therapeutic modalities. The prognosis can be determined by counting the copies of metadherin in a patient’s cell.
Background for Methods for identifying and treating cancers with a poor prognosis
The progression of cancer, from an abnormal growth to a potentially life-threatening tumor, is accompanied with a multitude of epigenetic and genetic alterations that accumulate along the way. It is difficult to distinguish between thousands of minor alterations and the drivers of cancer metastasis. Two parallel but incomplete genomic approaches have been developed to unravel the genetics behind cancer metastasis since the turn of the millennium.
The first method, which is based on a comparative analysis of expression profiles for cancer cell lines with different metastatic potentials (often obtained through in vivo selection of animal models), has led to several metastasis gene discoveries. There is still much to do to confirm the clinical relevance for metastasis gene identified in animal models.
The second approach, which involves gene expression profiling in tumor samples, allowed the identification of a number of poor-prognosis signs that can be used to predict recurrence or metastasis risks. Different poor-prognosis signs for the same cancer type identified in independent studies proved to be interchangeable in clinics. However, there is no gene overlap among the different signatures. This has made it difficult for scientists to understand the biological basis of cancer progression and metastasis. There is no universal “poor prognosis” gene. It is important to identify a genetic signature that can predict poor prognosis in all clinical classes.
Embodiments” of the present invention offer an objective way to predict the long-term outcomes of a cancer incident. The invention is a breast cancer-related embodiment. Other embodiments of the invention relate to immunotherapy and antisense therapy in order to combat cancer metastasis and inhibit the development cells resistant to chemotherapeutic drugs.
In one embodiment, this invention provides a treatment method for breast cancer and other cancers that includes: a. providing a subject suspected to have breast cancer or another cancer; b. administering an agent which inhibits the activity of metadherin.
The method can be used for cancers with a poor outcome, such as breast cancers or other cancers that are metastatic, chemoresistant, have more than two copies of the metadherin genes, or cancers that contain a cell with a copy number of the metadherin genome that is greater than a control, the control being a non-cancerous or reference cell.
In some embodiments, an agent can be selected from a group that includes a metadherin antibody, a Metadherin antisense molecular, and a small-molecule.
The invention provides, in a preferred embodiment of the invention, a method to determine a prognosis for an individual with breast cancer or another cancer. The method includes a) providing cancer cells from said subject; b) determining a copy number of the metadherin genes for said cell; and c), assigning a bad prognosis to that subject if this copy number is higher than 2.
The invention, in one embodiment, provides a method for reducing the growth of chemoresistant tumor cells in a patient treated with a chemotherapy agent. This method includes: a. administering a pharmaceutically-acceptable amount of the chemotherapeutic drug to the subject, b. administering an agent chosen from the group consisting an antisense molecule to metadherin and a small molecular.
In another embodiment of the invention, it provides a method for determining variations of the copy number of a gene in defined populations. It comprises the following steps.
In one embodiment, the method for determining variations of copy-numbers of a gene in defined populations involves finding a stretch 20 or more continuously aberrant neighborhood scores. This is to detect a genomic alteration of copy-number.
In one embodiment, the method for determining variations of the copy number of a gene in defined populations includes a neighborhood score that is greater than zero. This allows the detection of a genomic gain.
In one embodiment, the method for determining variations of copy-numbers of a gene in defined populations includes finding an neighborhood score lower than zero to detect genomic loss.
In some embodiments the invention provides a treatment method wherein the treatment agents are a combination of known chemotherapeutic agents and an antisense (which can be, without restriction, an shRNA, siRNA, or small molecule) or a molecule. In one embodiment, the treatment agent is administered in conjunction with the chemotherapeutic drug. In another embodiment, a treatment agent is conjugated with the chemotherapeutic drug. “In one embodiment, paclitaxel is the chemotherapeutic drug.
In another embodiment, the invention provides for a method to screen for anti-metastatic substances that comprises a) contacting with a cancer cell expressing Metadherin a test substance; and b), determining the likelihood of the cancer cell to metastasize based on a level of biological activation of metadherin relative to a level in the absence said test compound. In one embodiment, the metadherin-expressing cancer cell is in an organism, which may be a human or a non-human mammal.
In one embodiment, this invention provides a way to determine, based upon the copy number for the gene that codes metadherin, the probability that a person will survive a particular cancer.
In one embodiment, copy numbers are determined on-site. In another embodiment the copy number can be determined in vitro. In other embodiments, copy numbers can be determined using fluorescent in situ hybridization. “Comparative genomic hybridization (CGH), High Density Single Nucleotide Polymorphism genotyping (SNP), or Real-Time PCR” are other examples of how the copy number is determined.
In other embodiments of the invention, the antibodies are used in a treatment method for a cancer that is susceptible to a chemotherapeutic drug. The method includes (a) administering a chemotherapeutic drug in an amount that is pharmaceutically acceptable to the patient, and (b), administering an agent to the patient to inhibit the activity of metadherin. In certain embodiments, administering a pharmaceutically-acceptable amount of the chemotherapy agent to the subject, and also administering the aforementioned agents, provides a method for reducing the growth of chemoresistant cells in a patient treated with a chemotherapy agent.
In one embodiment, this invention provides a way to determine a cancer patient’s prognosis. This includes, but is not limited, to liver cancer, brain cancer, and prostate cancer. Metadherin can be expressed abnormally in certain cancers. In certain embodiments, a metadherin-specific antibody is administered to a patient at a dose sufficient for the metadherin to be detected. The art is familiar with antibody-mediated prognosis for cancer in humans, as shown in U.S. Pat. No. No. In certain embodiments, the invention provides for a method to treat cancer by inhibiting metadherin. Said cancers include but are not limited liver cancer, brain cancer, or prostate cancer. In certain embodiments, an anti-metadherin antibody is administered to an individual suffering from cancer in a dose sufficient to inhibit the metadherin or reduce the amount of the metadherin. For the present application, it is not required that metadherin be completely inhibited or reduced. The art is familiar with the treatment of cancer in humans by antibodies, as can be seen in U.S. Pat. No. No.
In some embodiments, a metadherin-binding antisense molecule (including but not restricted to mRNA or non-splicedRNA) is given to an individual suffering from cancer in a dose sufficient to inhibit metadherin and reduce the amount of metadherin. In certain embodiments, the antisense molecule can be an siRNA, a shRNA or RNAi molecule. For the present application, it is not required that there is a complete reduction or inhibition. The art is familiar with anti-sense treatments for cancer patients, such as U.S. Patent. No. No.
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