PIK3C Case Study

Advances in MDS therapy will derive from molecular precision and identification of potential druggable targets for the disease. In 2005, The Cancer Genome Atlas (TCGA), and during 2008, The International Cancer Genome Consortium (ICGC) were designed as large-scale projects to improve understanding of cancer associated recurrent somatic mutations. In AML, robust prognostic relevant mutations were reported with mutational subgroups frequently observed in MDS suggesting similar ability to detect a significant impact on MDS outcome. Seven subgroups including activating signaling, DNA methylation, chromatin modifiers, spliceosome, myeloid transcription factors, tumor suppressor genes, and less commonly observed mutations including cohesin complex, BCOR, and BCORL1 (Fig.3). In this section, we will describe frequency, prognostic and functional implication of

Background: cancer has developed mechanisms to survive and resist drugs including methotrexate, a DHFR inhibitor

It is now acknowledged that NSCLC is not a singular pathogen but is in fact multiple pathologies with unique molecular signatures that we are only beginning to understand and unravel . Widely speaking, the main subtypes are pulmonary adenocarcinoma, squamous cell carcinoma (SCC) and large cell carcinoma. This distinction alone allows for a more tailored selection of cytotoxic chemotherapy in advanced NSCLC without a controller mutation, as seen with enhanced efficacy with pemetrexed in adenocarcinoma or the toxicity concerns of bevacizumab in patients with squamous histology .

Results showed that VeriStrat® testing was able to identify a group of patients who have worse progression free survival (PFS) when treated with Femara alone, independent of Her2 status.

So, with this increase in toxicity over single agent inhibition of the PD-1 checkpoint, an increase in efficacy would be required to support development of the combination. At the doses of tremelimumab considered tolerable, among PD-L1 positive patients (based on staining in 25% of the cancer cells), the response rate does not appear superior to single agent PD-1 inhibition.2,4 However, among those without high level PD-L1 expression, 4 of 14 patients responded to the combination, while with approved agents, no more than 2 patients would anticipated to respond.2,4

Some of traditional drugs may be effective in patients whose cancers have a specific molecular target, and not for other patients. To solve this problem of patient-specificity, pharmaceutical research have seen the expansion of individually tailored cancer treatment, which is an application of targeted therapy, and this is where biopharmaceuticals are. As an increasing part of the population is diagnosed with cancer and as these patients live longer, increasing care will be given to patients who have received these drugs. Moreover, in the case of cancer therapy, those drugs and especially with mABs are a promise of less side effects : recombinant DNA technology makes it possible to genetically engineer an antibody to reduce the risk of host immune response.

For many types of cancers, we have been using the same base drug (first line treatment) for ten years or even longer. As companies find new drugs to fight the cancers, they hope that it will be the miracle drug that will eradicate the cancer, but it usually isn’t. When they reach this conclusion, instead of returning to the chalkboard and continuing to work to improve the drug, they put the drug on the market as is, and hope it will achieve something. Not only are they putting these drugs on the market but they put price tags on them that would bankrupt anyone without some sort of third party payer. The combination of all of these drugs make up what doctors

The book The Philadelphia Chromosome by Jessica Wapner follows the story of how a fatal disease called Chronic Myeloid Leukemia became one of the first targets of kinase inhibitors for targeted cancer therapies. Chronic Myeloid Leukemia (CML) affects only a small number of people (an estimated 8,500 diagnoses this year), but was until recently considered a fatal disease. Gleevec, a drug created by Novartis (mostly) that targeted the BCR/ABL protein in CML patients. This protein causes a tyrosine kinase to uncontrollably phosphorylate myeloid cells in bone marrow. The BCR/ABL protein is caused by a gene mutation known as The Philadelphia Chromosome, which is an abnormality in chromosome 22.

The antitumor efficacy of crizotinib was dose dependent and demonstrated a strong correlation to inhibition of c-Met phosphorylation. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of crizotinib [1].

In recent years, treatment options for advanced solid tumors have significantly advanced.1,2 Patients now routinely have their tumors genotyped in order to identify genomic markers that can allow their treatment to be personalized with targeted therapies that are less toxic and more effective. Prior studies have found that up to 64% of patients have these oncogenic drivers, and patients with these drivers in their tumors live longer when they are treated with targeted therapy.1 The Profile project was launched at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in 2011 as the platform for Precision Medicine. Profile provides detailed testing on tissue samples obtained during the course of clinical care for a panel of genetic

The established definition of rituximab resistance is the lack of response or the progression within 6 months of treatment to a rituximab-containing regimen.11 Continued disease progression during rituximab therapy is the most clearly defined form of resistance. Patients who experience tumor shrinkage may have some degree of rituximab sensitivity but can still be classified as “resistant” if they fail to achieve either a partial or complete response. Numerous pathways of tumor resistance have been elucidated with conventional chemotherapeutic agents. In some cases, these discoveries have translated into specific interventions intended to prevent or overcome tumor resistance.11 Surprisingly, little is known about the determinants of responsiveness and resistance to rituximab in the treatment of B-cell NHL.11 The exact mechanism(s) of rituximab’s action in patients, either as a single drug or in combination

The established definition of rituximab resistance is the lack of response or the progression within 6 months of treatment to a rituximab-containing regimen.11 Obvious disease progression during rituximab therapy is the most clearly defined form of resistance. Patients who may experience tumor shrinkage have some degree of rituximab sensitivity but are often classified as “resistant” if they fail to achieve either a partial or complete response. Numerous pathways of tumor resistance have been elucidated with conventional chemotherapeutic agents. In some cases, these discoveries have translated into specific interventions aimed at preventing or overcoming tumor resistance.11 Surprisingly, little is known about the determinants of responsiveness

Zhu conducted a study to compare the survival rate of patients with colorectal cancer and were treated with a systemic drug, which was oxaliplatin, and those who were treated with CRS-HIPEC. The study showed that those patients who received systemic chemotherapy had an average survival of 24 months, while those who received CRS-HIPEC had a survival of 63 months.16 Randomised studies and other cohort studies have provided encouraging information on the overall survival in patients who have undergone CRS-HIPEC treatment with or without early postoperative intraperitoneal chemotherapy (EPIC), as compared to those who obtained systemic

They analyzed the genetic profiles of these patients to study a concept known as the “double-hit hypothesis”, which is a widely accepted theory in the field of cancer.

The Phase II trial was randomized and placebo-controlled that enrolled 164 patients with previously untreated GI cancers. These patients received ramucirumab in combination with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) or a placebo plus FOLFOX. The main endpoint of the Phase II trials was to test progression free survival (PFS), but other end points also included overall response rate (ORR), safety, and overall survival. The results of these trials found that there was no improvement in PFS or median OS, but that there was a significant increase in disease control rate (management of metastasis), which allowed the drug to move to Phase III trials